Educational programs for preventing sexually transmitted infections (STIs) have often been implemented in different settings and populations. Mathematica Policy Research and Child Trends conducted a systematic review of 289 evidence-based interventions aiming to reduce STIs and sexual risk behavior in adolescents in the United States. These interventions were published between 1989 and 2012. We conducted a meta-analysis of the interventions that assessed incidence of STIs at follow up, and we identified key characteristics of successful interventions. Results showed that on average interventions reduced incidence roughly from 7 to 6 out of 100 people (17% relative risk reduction (RRR)). Interventions focused on abstinence had no effect, while comprehensive education programs aiming to improve skills and promote safe sexual practices reduced risk by 4 percent (23% RRR). In particular, interventions teaching condom use skills or communication and negotiation skills reduced incidence of STIs by 3 to 4 percent (30% RRR). Finally, interventions decreasing frequency of intercourse or number of sexual partners and interventions increasing condom use also reduced incidence of STIs by 5 to 7 percent (28-36% RRR). Overall properly designed interventions with the above-mentioned characteristics can achieve a 30% reduction of STI incidence. Implications for designing successful interventions to prevent STIs in adolescents are discussed.