Evidence-based, single-session behavioral interventions are urgently needed for preventing the spread of HIV and other sexually transmitted infections (STIs). To estimate the efficacy of single-session, behavioral interventions for STI prevention, we collected data from 29 single-session interventions (20 studies; n = 52 465) with an STI outcome. Infection with an STI was 35% less likely (odds ratio = 0.65; 95% confidence interval = 0.55-0.77) among intervention group participants than among control group participants. Single-session interventions offer considerable benefits in terms of disease prevention and create minimal burden for both the patient and the provider. Brief and effective STI prevention interventions are a valuable tool and can be readily adapted to bolster the benefits of biomedical technologies focusing on the prevention of HIV and other STIs. (Am J Public Health. Published online ahead of print September 20, 2012: e1-e7. doi:10.2105/AJPH.2012.300968).