Using a sample of 482 ethnically diverse current substance using men who have sex with men who reported recent unprotected anal intercourse, this study compared health risk behaviors-substance use and sexual HIV risk-and one health protective factor-prosocial activities-between men who live in a gay neighborhood and those who do not. Data are drawn from comprehensive health and social risk assessments administered in South Florida. In a multivariate logistic regression model, methamphetamine use, high rates of receptive unprotected anal intercourse, and lower levels of prosocial engagement were found to be risk factors associated with gay neighborhood residence. Compared with living elsewhere, gay neighborhood residence appeared to be protective against cocaine use and substance dependence. Implications of the findings for prevention interventions are discussed, as is the need for further research regarding decisions about neighborhood residence and how neighborhood risk and protective factors emerge and are sustained.