The present study evaluated the efficacy of Familias Unidas + Parent-Preadolescent Training for HIV Prevention (PATH), a Hispanic-specific, parent-centered intervention, in preventing adolescent substance use and unsafe sexual behavior. Two hundred sixty-six 8th-grade Hispanic adolescents and their primary caregivers were randomly assigned to 1 of 3 conditions: Familias Unidas + PATH, English for Speakers of Other Languages (ESOL) + PATH, and ESOL + HeartPower! for Hispanics (HEART). Participants were assessed at baseline and at 6, 12, 24, and 36 months postbaseline. Results showed that (a) Familias Unidas + PATH was efficacious in preventing and reducing cigarette use relative to both control conditions; (b) Familias Unidas + PATH was efficacious, relative to ESOL + HEART, in reducing illicit drug use; and (c) Familias Unidas + PATH was efficacious, relative to ESOL + PATH, in reducing unsafe sexual behavior. The effects of Familias Unidas + PATH on these distal outcomes were partially mediated by improvements in family functioning. These findings suggest that strengthening the family system, rather than targeting specific health behaviors, may be most efficacious in preventing and/or reducing cigarette smoking, illicit drug use, and unsafe sex in Hispanic adolescents.