PURPOSE: To examine perceptions of phase-I human immunodeficiency virus (HIV) vaccine trial participation among African-Americans and Hispanics in San Francisco, California. DESIGN: Qualitative, semistructured interviews. SETTING: San Francisco Department of Health. PARTICIPANTS: Thirty-six African-American and Hispanic men and women, 18 to 50 years of age, residing in the San Francisco Bay Area. METHOD: Purposive sampling using advertisements, community-based organization rosters, and snowball referrals. Thematic analysis of transcripts identified salient themes and patterns. RESULTS: Participants viewed participation in HIV research as important; however, they held that HIV was not a health priority given limited awareness about HIV research or beliefs that only infected or high-risk persons were eligible for participation. Altruism and personal gain, trustworthy trial staff, convenient schedules and facilities, and involvement of trusted community groups in recruitment were perceived to motivate participants. Concerns about the social consequences of participating in HIV research and product-related side effects were seen as discouraging participation. Limitations include the possibility that participants in interview research have more favorable views of biomedical research than those who refuse to participate. CONCLUSION: Historically, African-Americans and Hispanics in the United States have had limited participation in HIV trials. Understanding their perceptions of HIV biomedical research, identifying facilitators and barriers to participation, addressing misinformation about HIV, distorted risk perceptions, HIV stigma, and providing accessible opportunities to participate are imperative to ensure health equity and generalizability of findings.