We examined the relationship of community, interpersonal, and personal risk and protective factors to substance use among adolescents of parents with HIV (PWH). Families with HIV (n = 269 PWH and 409 adolescents) from New York City were recruited, and multivariate models were used to examine the associations. Adjusting for age, gender, and ethnicity, substance use was positively associated in univariate analyses with parental substance use, family conflict, adolescent emotional distress, and adverse life events; having academically oriented friends and religiosity were protective. In the multivariate model, multiple problem behaviors (e.g., delinquency) and substance-using peers were significantly associated with substance use. The patterns of associations between the risk factors and substance use are similar to those of adolescents in families not impacted by HIV. Interventions aimed at improving parental care, reducing maladaptive peer networks, and decreasing problem behaviors are important strategies to explore in future prevention studies.