Objectives: School-based sex education is a cornerstone of HIV prevention for adolescents who continue to bear a disproportionally high HIV burden globally. We systematically reviewed and meta-analyzed the existing evidence for schoolbased sex education interventions in low- and middle-income countries to determine the efficacy of these interventions in changing HIV-related knowledge and risk behaviors. Methods: We searched five electronic databases, PubMed, Embase, PsycInfo, CINAHL, and Sociological Abstracts, for eligible articles. We also conducted hand-searching of key journals and secondary reference searching of included articles to identify potential studies. Intervention effects were synthesized through random effects meta-analysis for five outcomes: HIV knowledge, self-efficacy, sexual debut, condom use, and number of sexual partners. Results: Of 6191 unique citations initially identified, 64 studies in 63 articles were included in the review. Nine interventions either focused exclusively on abstinence (abstinence-only) or emphasized abstinence (abstinence-plus), whereas the remaining 55 interventions provided comprehensive sex education. Thirty-three studies were able to be meta-analyzed across five HIV-related outcomes. Results from meta-analysis demonstrate that school-based sex education is an effective strategy for reducing HIV-related risk. Students who received school-based sex education interventions had significantly greater HIV knowledge (Hedges g = 0.63, 95% Confidence Interval (CI): 0.49–0.78, p,0.001), self-efficacy related to refusing sex or condom use (Hedges g = 0.25, 95% CI: 0.14–0.36, p,0.001), condom use (OR = 1.34, 95% CI: 1.18–1.52, p,0.001), fewer sexual partners (OR = 0.75, 95% CI:0.67–0.84, p,0.001) and less initiation of first sex during follow-up (OR = 0.66, 95% CI: 0.54–0.83, p,0.001). Conclusions: The paucity of abstinence-only or abstinence-plus interventions identified during the review made comparisons between the predominant comprehensive and less common abstinence-focused programs difficult. Comprehensive school-based sex education interventions adapted from effective programs and those involving a range of school-based and community-based components had the largest impact on changing HIV-related behaviors.