Worldwide, young people aged 15–24 accounted for almost half of all new HIV infections among individuals aged 15 and older in 2010. As sexual debut is common in adolescence, so are the associated risks of engaging in transactional sex, having multiple concurrent partnerships, and experiencing sexual violence and coercion, all of which increase HIV-related risk. School-based sex education is a cornerstone of HIV prevention for adolescents who continue to bear a disproportionally high HIV burden globally. This systematic review provides existing evidence for school-based sex education interventions in low- and middle-income countries to determine the efficacy of these interventions in changing HIV-related knowledge and risk behaviors.