Most drug abuse prevention research has been conducted with predominantly White middle-class adolescent populations. The present study tested a school-based drug abuse preventive intervention in a sample of predominantly minority students (N = 3,621) in 29 New York City schools. The prevention program taught drug refusal skills, antidrug norms, personal self-management skills, and general social skills in an effort to provide students with skills and information for resisting drug offers, to decrease motivations to use drugs, and decrease vulnerability to drug use social influences. Results indicated that those who received the program (n = 2,144) reported less smoking, drinking, drunkenness, inhalant use, and polydrug use relative to controls (n = 1,477). The program also had a direct positive effect on several cognitive, attitudinal, and personality variables believed to play a role in adolescent substance use. Mediational analyses showed that prevention effects on some drug use outcomes were mediated in part by risk-taking, behavioral intentions, and peer normative expectations regarding drug use. The findings from this study show that a drug abuse prevention program originally designed for White middle-class adolescent populations is effective in a sample of minority, economically disadvantaged, inner-city adolescents.