Culturally-specific HIV risk reduction interventions for Hispanic women are needed. SEPA (Salud/Health, Educación/Education, Promoción/Promotion, y/and Autocuidado/Self-care) is a culturally-specific and theoretically-based group intervention for Hispanic women. The SEPA intervention consists of five sessions covering STI and HIV prevention; communication, condom negotiation and condom use; and violence prevention. A randomized trial tested the efficacy of SEPA with 548 adult U.S. Hispanic women (SEPA n = 274; delayed intervention control n = 274) who completed structured interviews at baseline and 3, 6, and 12 months post-baseline. Intent-to-treat analyses indicated that SEPA decreased positive urine samples for Chlamydia; improved condom use, decreased substance abuse and IPV; improved communication with partner, improved HIV-related knowledge, improved intentions to use condoms, decreased barriers to condom use, and increased community prevention attitudes. Culturally-specific interventions have promise for preventing HIV for Hispanic women in the U.S. The effectiveness of SEPA should be tested in a translational community trial.