Healthy Choices is a motivational interviewing intervention targeting multiple risk behaviors among HIV-positive youth. This study investigated the effects of this intervention program specifically on alcohol and marijuana use. Youth living with HIV (n = 143, mean age = 20.7, 51.5% male) were recruited from four sites in the United States, and randomly assigned to intervention or control conditions. The four-session intervention focused on two of three possible problem behaviors based on entry screening; this study focused on 143 HIV-positive youth who received the intervention for substance use. At 15-month follow-up past-week alcohol use was significantly lower for intervention youth than control youth (39.7% versus 53.6%, χ2 = 2.81, 0.05 < p < 0.01); developmental trajectory analysis demonstrated significant reductions in alcohol use, but more importantly the intervention was effective over time in significantly reducing the adolescent's probability of being classified into the high-risk trajectory group. The intervention was less effective in reducing marijuana use.