For pre-exposure prophylaxis (PrEP) and microbicides to effectively prevent HIV, optimal treatment adherence is required. Adherence to these strategies, however, has not been sufficiently studied. This investigation systematically reviews oral PrEP and microbicide trials across 4 domains of adherence: (1) definition and measures used, (2) risks for nonadherence, (3) promotion strategies, and (4) effects on outcomes. Nineteen (n = 19) trials, with 47,157 participants, published between 1987 and 2012 were identified. Reported mean adherence to microbicides was 79% and to oral PrEP 87%. Common risks for microbicide nonadherence were decreased motivation over time, sex with primary (noncommercial/casual) partners, and insufficient supply. Oral PrEP nonadherence risks were older age and medication side effects. Psychoeducation and outreach to participants and communities were frequently used promotion strategies. Most trials failed to systematically identify barriers and monitor and promote adherence, although adherence moderated outcomes. Recommendations for attending to adherence in future trials are provided.