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Few HIV prevention interventions have been evaluated in randomized controlled trials (RCTs). We examined design, implementation, and contextual considerations that may limit detection of a positive or adverse effect in HIV prevention trials.A systematic review of late phase RCTs for prevention of sexual transmission of HIV that randomly allocated intervention and comparison groups; evaluated interventions to prevent sexual transmission in nonpregnant populations; and reported HIV incidence as the primary or secondary outcome.PubMed/MEDLINE, other electronic databases, and electronic conference proceedings of recent HIV/AIDS-related conferences were searched to identify published or unpublished trials meeting the inclusion criteria. Descriptive, methodological, and contextual factors were abstracted from each trial.The review included 37 HIV prevention RCTs reporting on 39 unique interventions. Only six RCTs, all evaluating biomedical interventions, demonstrated definitive effects on HIV incidence. Five of the six RCTs significantly reduced HIV infection: all three male circumcision trials, one trial of sexually transmitted infection treatment and care, and one vaccine trial. One microbicide trial of nonoxynol-9 gel produced adverse results. Lack of statistical power, poor adherence, and diluted versions of the intervention in comparison groups may have been important issues for the other trials that demonstrated ‘flat’ results.Almost 90% of HIV prevention trials had ‘flat’ results, which may be attributable to trial design and/or implementation. The HIV prevention community must not only examine evidence from significant RCTs, but must also examine flat trials and address design and implementation issues that limit detection of an effect.