Background: Peer-education programmes aim to bring about attitudinal and behavioural changes in their target audience. In the South African educational context, peer education is a favoured approach in dealing with issues such as HIV and AIDS, sexual decision-making and substance misuse. Given the reliance on peer-education programmes in the educational system, it is important to establish how well they are working. This study aims to assess the effect of an extensive, structured, time-limited, curriculum-based, peer-led educational programme on first-year high school learners in public schools in the Western Cape Province of South Africa. Method: The curriculum called ‘Listen Up’ addresses issues such as supporting peers, sexual decision-making, healthy relationships, HIV risk, alcohol misuse and unwanted pregnancy in seven structured sessions. The programme targeted adolescents in Grade 8 growing up in what are considered to be risky environments in public schools in the Western Cape during 2012 and 2013. The intervention was evaluated based on 10 scales sourced from published literature related to the outcome indicators of future orientation, sensation-seeking, self-efficacy in sexual relations, HIV transmission knowledge, HIV prevention knowledge, HIV attitudes, sexual attitudes, decision-making, healthy relationships and social support. Descriptive statistics were used to analyse demographic and community characteristics and analyses of variance were used to detect differences between groups. The surveys were administered to a total of 7709 learners across three waves of the study in 27 peer intervention schools and eight control schools. Results: Immediately post intervention, statistically significant differences were noted for the intervention schools when compared to their baseline levels on measures of future orientation, self-efficacy in sexual relations, knowledge regarding HIV transmission, knowledge regarding HIV prevention and knowledge in terms of healthy relationships. Comparing baseline values with results collected between five and seven months post intervention, statistically significant results were noted for self-efficacy in sexual relations and knowledge regarding HIV transmission. Conclusion: The findings of this study suggest that peer-education can improve adolescents’ self-efficacy in sexual relations as well as knowledge regarding the transmission of HIV and therefore can contribute to the prevention of HIV transmission among adolescents.