Background: In 2012, an estimated 2.1 million adolescents were living with HIV. Though there are effective interventions to prevent and treat HIV infection, adolescents face specific barriers in accessing them. As a result, new infections and poor outcomes among HIV-infected adolescents are common. HIV programming for adolescents should focus on interventions of proven effectiveness and address underlying factors driving incidence and lack of effective treatment and care in this age group. Methods: We conducted a systematic review of systematic reviews to summarize the global data on effectiveness of 20 intervention types, to identify characteristics of effective interventions, and to explore evidence of how adolescents can access interventions with proven effectiveness. Interventions were in 2 broad categories: those designed primarily for adults and those designed specifically for adolescents. Where available, we evaluated the evidence of impact on the key outcomes: HIV risk, HIV transmission, and HIV morbidity and mortality. Results: Among the interventions designed for adolescents, there was high-quality evidence that in-school interventions and some interventions in geographically defined communities can positively impact important HIV-related outcomes, such as self-reported sexual risk behaviors. Interventions designed primarily for adults that had high-quality, consistent biological evidence of efficacy included voluntary medical male circumcision (VMMC), antiretrovirals for the prevention of mother-to-child transmission, HIV testing and counseling, HIV treatment, condom use, and provision of sterile injecting equipment to people who inject drugs. There was also an evidence of potential efficacy for oral preexposure prophylaxis and behavior change interventions among certain populations. There was a dearth of systematic review data on how best to enable adolescents to access the intervention types identified as having proven effectiveness among adults. Conclusions: This series of reviews allowed us to rigorously and systematically review a large number of intervention types at once using a standard, transparent methodology. Eight key interventions showed clear evidence of effectiveness, with evidence of potential efficacy for some additional interventions among certain populations. Discussion: These priority interventions with proven effectiveness should be included in all HIV prevention programming for adolescents. There is a pressing need for more rigorous research on how best to enable adolescents to access these effective interventions.