Six Degrees of Separation opened in New York City in 1990 and was an immediate critical and popular success. Outstanding reviews and full houses greatly extended the play's original ten-week run. Eva Resmkova, writing in the National Review, called it "the lone original American play of the season." Guare's play went on to win the New York Critic Circle Award for Best Play of the Year and London's Olivier award, and to be nominated for a Tony Award. In the New York Times, Frank Rich wrote that viewing Six Degrees of Separation was "a transcendent theatrical experience that is itself a lasting vision of the humane new world of which Mr. Guare and his New Yorkers so hungrily dream.''

Critics applauded the actors, the characters, and Guare's imagination and skill. Newsweek reviewer Jack Kroll wrote of Paul, he "is a major creation: he's a figure of dizzying ambiguity, weirdly innocent, sexually seductive, socially unsophisticated, startlingly insightful.'' Rich further called the play a "masterwork" in his review. "Among the many remarkable aspects of Mr. Guare's writing," he added, "is the seamlessness of his imagery, characters and themes, as if this play had just erupted from his own imagination in one perfect piece." Indeed, as Guare wrote in his Production Note to the published version of the play, he completed Six Degrees of Separation "very quickly" but was "[A]rmed with a lot of preparation."

The play is loosely based on real events reported in the New York papers in 1983. Guare uses the actual occurrence of a young African-American man who maneuvered himself into the households of wealthy New Yorkers as his starting point to explore human relationships, particularly in the American family. This issue has been of primary concern to Guare throughout his career. As Tish Dace pointed out in Contemporary Dramatists, Six Degrees of Separation contains that element so crucial to Guare's work, "dramatizing... the love/ hate relationships in the American family." She further remarks on Guare's technique:

His freewheeling imagination unfettered by the constraints of realism as he employs such presentational devices as narration, soliloquies and asides to the audience, and poetic speech, Guare nevertheless grounds his play in contemporary American life, especially the sudden end of a family unit.

The play delves into issues critical to modern life. As William A. Henry in noted in his review in Time, the story "takes on deep resonances." Resnikova called it partly a "comedy of manners" and partly a "morality tale.'' Other critics noted its farcical and satirical nature, techniques that are integral to much of Guare's work.

In his body of work, Guare frequently deals with metamorphosis, parent-child relationships, and violence, and Six Degrees of Separation is no exception. Ouisa Kittredge, who is alienated from her children, finds in Paul a substitute child, even remarking that "[H]e did more for us in a few hours than our own children ever did." The dissatisfaction of the relationships in the Kittredge family is made clear by Ouisa's interest in Paul, who is an acknowledged liar.

One of the most important themes raised by the play is the ambivalent feelings that the rich feel for the poor. As Henry pointed out, the play shows "liberals' fantasies of rescuing the poor." As aptly demonstrated by the Kittredges's actions, these fantasies go unfulfilled. The Kittredges are also unsure of how to respond to Paul as a young African-American man. Wrote Henry, "the encounter devastatingly sketches the uneasy state of U.S. race relations, in which white liberals may endorse the black cause in theory, yet not know any blacks socially and thus fawn on or patronize them." Henry referred to Paul's "analysis" of The Catcher in the Rye as an example of this, "the hosts are spellbound by his vocabulary and miss the fact that his rap becomes comic nonsense.''

The play also brings up other sources of conflict: class issues, generational disagreements, sexual orientation, and race. The characters' dysfunction demonstrates that these are simply more places for modern humanity to become isolated from others.