- Mark Greene: First wife cheats on him and leaves him for the other man. Susan leaves him before they can even have a relationship. He grossly mishandles a routine delivery (compounded by a complete lack of help from anyone in obstetrics), resulting in the mother's death. Gets the crap beaten out of him by an unknown assailant. Has a distant relationship with his tough military father. Loses his mother to dementia and eventually loses his father to lung cancer. Suffers a brain tumor. Oldest daughter becomes a rebellious brat, leading to his infant daughter nearly dying of a drug overdose, before he finally dies from a recurrence of his brain tumor, leaving both daughters without a father during their formative years. This was why his actor, Anthony Edwards, played Brains in the infamous 2004 movie Thunderbirds—he needed a bright, optimistic project like it, having been emotionally drained by his tenure here.
- Doug Ross: Was abused and eventually abandoned by his father, emotionally damaging him so much that for years, he's unable to maintain a healthy relationship with a woman, costing him the woman he loves (for a time). Suffers through Carol's suicide attempt and her rejection of him afterwards. Hits rock-bottom after one of his one-night stands dies, nearly costing him everyone's personal and professional respect. Father dies without him ever getting a chance to reconcile with him or tell him off. Then after finally getting his life together—reconciles, proposes to,and moves in with Carol, receives a promotion at work—he blows it by being involved in the Mercy Kill of one of his patients, forcing him to resign and leave town in disgrace, then spends a year and half away from his beloved Carol, missing out on the birth of his children and the first few months of their lives.
- Susan Lewis: Her boyfriend suffers a breakdown and mysteriously disappears without a trace, only for it to be revealed months later that he's run off with another woman. She's constantly hounded by Jerkass senior physicians (to his credit, one of them apologizes after she saves his life). It's implied she's spent her entire life picking up after her perpetually screwing up older sister, including caring for her baby after she abandons the child. Comes to care for her niece as if she were her own daughter, only to lose custody of her when her newly-reformed sister reappears. Sees a therapist to deal with said loss. Develops feelings for her best friend, but then has to leave him before they can have a relationship. When she comes back, he's married with a child. She then has to grapple with the thought of him dying. Loses out on a tenured position because, unlike the affluent Carter, she cannot secure sufficient grant funding.
- John Carter: Constantly trod on by his mentor Benton as a student and resident. Loses a friend to suicide and grapples with guilt over not being there for him. Has numerous relationships fail. Gets literally stabbed in the back by a deranged patient and is forced to watch Lucy Knight bleed out next to him. The fallout of the attack eventually leads him to become addicted to painkillers, for which the ER staff force him to check into rehab. His mentor leaves the hospital to join private practice. His own child ends up being a stillbirth and even as the series ends, his relationship with the child's mother is left ambiguous. He suffers from chronic kidney problems as a result of the stabbing, leading him to require a transplant.
- Peter Benton: Despite being a skilled physician, is in complete denial about how ill and frail his mother is becoming. Cannot break away from the hospital to spend time with his mother (even missing her birthday to save a Neo-Nazi from a stab wound to the chest). Feels responsible for her injuries when he falls asleep while looking after her and she promptly falls and breaks her hip. Suffers a Heroic BSoD when she dies a few months later. Falls in love with her Physician Assistant but she rejects him twice, first when he's bereaved over the loss of his mother, second in favour of her (adulterous) husband, finds out a few weeks later that she left her husband, then goes through an HIV scare when she reveals that she's HIV-positive. Is shunned by fellow staff members when he blabs about co-workers mistakes. Is guilt-ridden over an underling's suicide (he hounded him mercilessly). Son is born prematurely, then ends up suffering a hearing impairment. Becomes temporarily blacklisted from practising after angering Romano. Learns that son isn't biologically his and nearly loses him in a custody battle.
- Carol Hathaway: Tries to commit suicide after being jerked around by Doug. Tries to adopt an AIDS-stricken little girl (who had no one to take care of her) only to have her efforts blocked because of said suicide attempt. Gets left at the altar when her fiancé correctly deduces that she doesn't really love him and is still in love with Doug. Has to dump another boyfriend when he refuses to admit that he even has PTSD (regarding the death of his friend) much less get help for it. Suffers a Heroic BSoD when Doug reveals that he has to leave her in season 5.
- Jeanie Boulet: Contracts HIV from her unfaithful husband (and ends up seeing him die, as she reveals that he passed away with a weight of 78 pounds) and promptly spends years fearful of embarking on a relationship because of this. Reunites with her adulterous husband only to be separated from him once again when he can only find work in Atlanta. Becomes friends with Anspaugh's twelve year old son, only to see him finally succumb to his constantly recurring cancer.
- Kerry Weaver: Mother gave her up for adoption, leading her to wonder for many years if it was because of her birth defect. Suffers a massive inferiority complex which seems to manifest itself in her need to overachieve at work and to back stab almost everyone. Is disliked by most of her colleagues. Undergoes a crisis in discovering her sexuality, and witnesses her girlfriend Sandy die from injuries sustained in a fire, then battles her homophobic family for custody of their son. Finally meets her birth mother only to find that she is a Conservative Christian fundamentalist and cannot love her or accept her because of her belief that homosexuality is wrong.
- Elizabeth Corday: Begins a relationship with Benton that ends when he more-or-less refuses to support her. Has her fellowship terminated by Romano because she wouldn't go out with him. Has to re-do her internship to stay in America, leading to her being over-worked and exhausted and, as a result, almost lethally injecting a patient with a fatal dose of magnesium. Sees her husband Mark succumb to his brain tumor and realizes just how alone Romano was when she ends up being the only one to show up to his funeral.
- Luka Kovac: Feels Survivor Guilt following the death of his wife and children, in part because he feels responsible for their deaths (not leaving Croatia early enough and staying to administer CPR to his dying daughter when his wife was bleeding out). Started to recover when he fell in love with Carol Hathaway, only to be setback when she broke his heart by leaving town to be reunited with Doug. Then he suffered a Heroic BSoD after killing a man who was attacking him and Abby, leading them to have a thoroughly dysfunctional relationship, then battled depression that culminated in him nearly killing a co-worker in a car accident. Not until he went to Africa did he get his act together, and even then, he almost died over there.
- Jing-Mei Chen: Suffers a Heroic BSoD after almost killing a patient as a medical student, forcing her to realize that she doesn't have what it takes to be a doctor. Has to endure pregnancy, childbirth, and giving her baby up for adoption alone because she has no real relationship with the baby's father, and because of her disapproving family—the child is part African-American. Is turned down for the coveted position of Chief Resident, then after appealing and getting the job, bungles it within weeks with a misdiagnosis that leads to a patient's death. This leads to a harsh rebuke from Weaver, as well as Weaver backstabbing her to ensure that she takes all the blame for the incident. Becomes so stressed by her the status of her ailing father that she lets him convince her to fatally inject him with Potassium.
- Abby Lockhart: Suffered a rough childhood, due in large part to her mother suffering from bipolar disorder (as did her brother, who she frequently had to look after). Ended up with a drinking problem that plagued her all throughout the show, frequently jeopardizing her career and relationships. Got shot whilst carrying her and Luka's child, putting both mother and son in jeopardy.
- Greg Pratt: Continuously passed over for promotion to Chief of Emergency Medicine. After finally being given the position, he dies after suffering injuries from an ambulance explosion. Because of Rule of Drama, Pratt died the very same day he was going to propose to his girlfriend and before his superiors had a chance to inform him he'd gotten the job as chief of the ER.
- Ray Barnett: Raised by an abusive stepfather who had an issue with substance abuse. Has to endure many of his friends being critically injured or even dead in the Season 11 finale. Gets kicked out of his band midway through Season 12. Frequently suffers from his unrequited love for Neela in Seasons 12 and 13—first when she's married to Gallant and then when she enters a meaningless relationship with Gates. Right when Neela finally reciprocates his feelings, he gets run over by a truck and loses both of his legs in the Season 13 finale.
- Archie Morris: Is (initially) an incompetent screwup who no one likes or respects. After getting his act together, gets kidnapped by a teenager in season 14 (so that Archie could operate on his girlfriend). Comes to bond with the kid during the course of their time together, only to see the young man get killed by a sniper bullet. Witnesses his best friend Greg Pratt die after suffering injuries from an ambulance explosion.
- Tony Gates: Raised by an alcoholic father. Gets badly injured by an explosion and Neela has to operate on him out in the field. Is manipulated by Meg to sleep with her because she'd paid for his tuition. Meg commits suicide when he decides to leave her for Neela, but not before informing him that Sarah is his. After getting his hopes up, a paternity test reveals that Sarah isn't his, and he loses a custody battle with her grandparents.
- Catherine Banfield: Revealed to have lost her young son to acute leukemia, something that she didn't recognize until pointed out by Dr. Greene, leaving her immensely guilty. She grows distant from her husband for a time before reconciling on the anniversary of their son's death. Goes through attempts to have another baby in the final season, with difficulty.
Woobie / ER