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Racial and ethnic minorities are disproportionately affected by HIV/AIDS in the United States despite advances in prevention methodologies. The goal of this study was to systematically review the past 30 years of HIV prevention interventions addressing racial disparities. We conducted electronic searches of Medline, PsycINFO, CINAHL, and Cochrane Review of Clinical Trials databases, supplemented by manual searches and expert review. Studies published before June 5, 2011 were eligible. Prevention interventions that included over 50% racial/ethnic minority participants or sub-analysis by race/ethnicity, measured condom use only or condom use plus incident sexually transmitted infections or HIV as outcomes, and were affiliated with a health clinic were included in the review. We stratified the included articles by target population and intervention modality. Reviewers independently and systematically extracted all studies using the Downs and Black checklist for quality assessment; authors cross-checked 20% of extractions. Seventy-six studies were included in the final analysis. The mean DB score was 22.44–high compared to previously published means. Most of the studies were randomized controlled trials (87%) and included a majority of African-American participants (83%). No interventions were designed specifically to reduce disparities in HIV acquisition between populations. Additionally, few interventions targeted men who have sex with men or utilized HIV as a primary outcome. Interventions that combined skills training and cultural or interactive engagement of participants were superior to those depending on didactic messaging. The scope of this review was limited by the exclusion of non-clinic based interventions and intermediate risk endpoints. Interactive, skills-based sessions may be effective in preventing HIV acquisition in racial and ethnic minorities, but further research into interventions tailored to specific sub-populations, such as men who have sex with men, is warranted.