Cecily — Cecily is the object of William's affections and poetic efforts in life; her rejection makes him open to Drusilla's seduction and subsequent siring. Centuries later, Spike sees Cecily as Halfrek, a vengeance demon, when they meet again over a century later in the episode "Older and Far Away." Spike does not recognize her, but Halfrek does and says William, the name that she knew him by in the past.

Drusilla — While vampires do not usually indulge in "love" (which reeks of humanity), Spike and Dru are a devoted couple for over a century. They spend their time traveling, feeding, and enjoying themselves. While Spike is single-mindedly devoted to her, Dru is never consistently faithful (maintaining a sexual relationship with Angelus despite Spike's obvious jealousy and discomfort, and, along with Darla, fornicating with the Immortal). She becomes disillusioned with Spike after his betrayal of Angelus, and she perceives his growing feelings for Buffy, and cheats on him with a Chaos Demon ("All slime and antlers!") in South America before breaking up with him, which sends him into a deep depression. By the time Drusilla returns to Sunnydale to reclaim her former love, Spike attempts to stake her to prove his love for Buffy, but Buffy tells him it would prove nothing and Spike cannot go through with it. Drusilla is disappointed at Spike's actions and departs from him.

Harmony Kendall — Spike and Harmony are involved from Season Four through early Season Five of Buffy. Despite Harmony's obvious adoration of him, Spike frequently ignores and mistreats her, even staking her to test out the Gem of Amara (an act which she did not forgive for some time) in the episode "The Harsh Light of Day". Although he tolerates her annoying habits in return for sex, his constant abuse, endless broken promises, and growing obsession with Buffy eventually bring about their break-up. Spike celebrates his re-corporealisation in Angel Season Five by having sex with Harmony, largely because she was the nearest female available, but she becomes possessed and attacks him. Harmony's embarrassing nicknames for Spike, which incude "Blondie Bear" and "Boo Boo", are later picked up and used at Spike's expense by Angel and Gunn.

Buffy Summers — Spike reluctantly becomes Buffy's ally during Seasons Two and Four, and in Season Five realizes he has fallen in love with her. Despite Buffy's initial repulsion at his feelings for her, she sees another side to him in "Intervention" and begins to regard him as an ally. In Season Six, they enter into a sexual relationship which ends badly, primarily because Spike seeks love and intimacy while Buffy merely wants physical comfort. After they break up, Spike tries to rape her, and this aborted attack becomes the catalyst which drives Spike to regain his soul. When she begins to trust him again, they develop a deep friendship, and his support of her, when all others abandon her, grants her the courage and strength to take the first step in destroying the Hellmouth. Spike dies in the Hellmouth believing that Buffy did not love him, although she earlier confessed to Angel that she had him in her heart. In the fifth and final season of Angel, Spike decides not to let Buffy know he has been resurrected because he wants her to remember him as a hero who died to save the world. He intends to meet up with her in Rome, where he and Angel are attempting to prevent a demon war, but their paths never quite cross.

Buffybot — After being rejected by Buffy, Spike commissions Warren to build him a robotic replica of Buffy to be single-mindedly devoted to him. Although he initially enjoys the toy, it is damaged in a fight with Glory. After Buffy's death, Willow reprograms the robot, and it becomes a useful and important tool in the fight against evil until Buffy's resurrection, although bits of the original programming occasionally resurface, causing Spike, who is deep in mourning for Buffy, significant pain.

Anya Jenkins — Spike and Anya bond over their mutual loss of demonic powers in the episode "Where the Wild Things Are." Later, in Season Six, after Xander leaves Anya at the altar and Buffy discontinues her relationship with Spike, they seek solace in one another in a drunken sexual encounter at the Magic Box in the episode "Entropy." They later flirt and argue in the Season Seven episodes "Beneath You", "Sleeper", and "Get It Done", with Anya joking about having sex during a night out.

Joyce and Dawn Summers — Spike treats Buffy's mother Joyce with continuing (and uncharacteristic) affection, honoring her kindness to him even after she dies. Following his painful break-up with Drusilla, she offers him hot chocolate and a shoulder to cry on, and they later bond over their mutual love of Passions in the episode "Checkpoint". While discussing his character's relationship with Joyce, James Marsters laughs, "Well, Spike, just maybe he just needs a mom. Maybe sometimes he just needs some chocolate milk and a little mom's love." Spike's relationship with Buffy's sister Dawn is that of a big brother/father figure. He continues to care for his "lil' bit" after Buffy's death, which, according to Marti Noxon in her commentary for "Bargaining", convinced many fans that he was genuinely good.

Willow Rosenberg — Spike confesses his attraction to Willow in episode "The Initiative", offering to sire her rather than simply kill her ("I can let you stay dead... or... bring you back, to be like me."). When Spike becomes an ally to the Scoobies, their relationship remains more or less friendly, with Spike inferring for himself that Willow is gay. Willow often defends Spike against angry prejudices of other Scoobies (mostly Xander's and Buffy's). Spike, on his part, is highly respectful of Willow's power as a witch, as well the depth of her love for her girlfriend Tara; following Glory's attack on Tara in "Tough Love", he asks Buffy "So you're saying that... a powerful and mightily pissed-off witch... was plannin' on going and spillin' herself a few pints of god blood until you, what, 'explained'?" He also shows a sincere preoccupation about her ever-growing addiction to magic, intervening slightly on her behalf in a confrontation with Anya (cf. "Older and Far Away"). Spike calls Willow "Red", usually in a fond way.

Faith Lehane — Spike and Faith first meet in the Buffy Season Four episode "Who Are You?". Faith has heard of Spike and flirts with him teasingly, but he believes her to be Buffy after she switched bodies with her fellow Slayer. The next time they meet, in the Season Seven episode "Dirty Girls", they fight and later acknowledge their previous encounter with good humour. Drew Goddard reveals in his commentary for that episode that this scene was created to showcase Faith and Spike's relationship, as Spike was originally intended to appear as a main character in the planned Faith spin-off. However, such a spin-off never materialised, so their relationship never progresses further, although later in Season Seven, they exchange blows over Faith's perceived betrayal of Buffy.

Andrew Wells — Andrew appears to have a crush on Spike, being mesmerised by the sight of him having sex with Anya in "Entropy" and imagining him shirtless in "Storyteller." The two later bond over their mutual love of onion blossoms and play "amusing games" together while on a mission to discover more about Caleb. Andrew is deeply affected by Spike's death, requiring therapy to cope with the loss, and is overjoyed to find him alive in "Damage." Spike, while not returning Andrew's romantic feelings, does appear to have some exasperated affection for him, putting up with multiple hugs and claiming that "there's hope for the little ponce yet" after hearing how he stood up to Angel.

Winifred Burkle — When he first meets Fred early in season five of Angel, Spike initially flirts with her, but his feelings quickly evolve into affection and esteem. Fred is the first person in Los Angeles who believes that he is "worth saving" and she works tirelessly to find a way to recorporealize him (while denying being taken in by his charm). Spike sacrifices a chance at becoming corporeal to save Fred's life, and he later chooses to remain at Wolfram & Hart in tribute to her sacrifice. Spike says in the episode "A Hole in the World" that he loves her, albeit in a platonic way.

Illyria — While their relationship is not romantic, Illyria and Spike share an emerging bond; each is on a path from demon to hero, and they share a love of violence. Their sparring sessions are mutually satisfactory; Spike hones his fighting techniques and Illyria is able to regularly inflict pain and dominate in combat. She, at one point, expresses a desire to keep Spike as a pet. After Illyria's powers are diminished, Spike helps her regain confidence and venture into the world again, the two teaming up to defeat a demon that is after Drogyn. Their relationship remains non-romantic, but develops into mutual respect.