Crack/cocaine and engagement in risky sexual behavior represent important contributors to the escalation of the HIV infection among women. Several lines of research have emphasized the role of social factors in women's vulnerability for such practices and stressed the importance of understanding such factors to better inform prevention efforts and improve their effectiveness and efficiency. However, few studies have attempted to pinpoint specific social/contextual factors particularly relevant to high-risk populations such as female crack/cocaine users. Extensive previous research has related the experience of social rejection to a variety of negative outcomes including, but not limited to, various forms of psychopathology, self-defeating, and self-harm behavior. Motivated by this research, the current study explored the role of laboratory-induced social rejection in moderating the relationship between gender and risky sexual behavior among a sample of crack/cocaine users (n = 211) at high risk for HIV. The results showed that among women, but not among men, experiencing social rejection was significantly associated with a greater number of sexual partners. Further, experiencing social rejection was not related to the frequency of condom use. Implications for future research, prevention, and treatment are discussed.