Set in 1987, it follows a suburban housewife in Los Angeles whose monotonous life is abruptly changed when she becomes sick with a mysterious illness which she believes is caused by the environment around her.

After the family's home is renovated, Carol begins experiencing physical symptoms in everyday situations: She coughs uncontrollably when exposed to exhaust fumes from a nearby truck while driving, has breathing difficulties at a baby shower, and suffers from a nosebleed while getting a perm at a hair salon.

Realizing that she can no longer function in her current life, she leaves everything behind and moves to Wrenwood, a new-age desert community for people with "environmental illnesses."

[12] For the script, Haynes has said that the conceptual origin involved setting up barriers that prevent the audience from getting emotionally close to the character of Carol, which was a concept he explored again in Far from Heaven.

[16] Cinematographer Alex Nepomniaschy suggested the look of Red Desert to Haynes after reading the script, and together they decided never to let the camera get very close to any of the characters as a way to keep emotional distance.

The website's critics consensus reads, "Safe's eerie social satire and somewhat sterile stylization is balanced by comedic undertones and an impressive, understated performance from Julianne Moore.

Another problem, according to Maslin, is that "the shadow of AIDS implicitly hangs over …[Carol's] decline, but it doesn't help bring Safe to a conclusion worthy of its inspired beginning.

"[26] The ending of the film is highly ambiguous, and has created considerable debate among critics and audiences as to whether Carol has emancipated herself, or simply traded one form of suffocation for an equally constricting identity as a reclusive invalid.

[27] Julie Grossman argues in her article "The Trouble with Carol" that Haynes concludes the film as a challenge to traditional Hollywood film narratives of the heroine taking charge of her life, and that Haynes sets Carol up as the victim both of a male-dominated society, and also of an equally debilitating self-help culture that encourages patients to take sole responsibility for their illness and recovery.

[28] Carol's illness, although unidentified, has been seen as an analogy for the 1980s AIDS crisis, a similarly uncomfortable and largely unspoken "threat" during the Reagan presidency.

[30] They Shoot Pictures, Don't They?, a website which gathers critics' polls, has also found Safe to be the 415th most acclaimed movie of all time.