Aims: Action to prevent the spread of HIV among young people in Sub-Saharan Africa is needed urgently. In order to be effective, such action should be theory and evidence based and carefully adapted to local cultures and contexts. The present article describes the organization, theoretical basis, and methodological approach of a project that aims at developing and evaluating school-based interventions targeting adolescents aged 12-14 years. Methods: Researchers from European and African universities have developed interventions that were conducted in three sites: Cape Town and Polokwane (South Africa) and Dar es Salaam (Tanzania). In each site the interventions were evaluated through large-scale field experiments with intervention schools and delayed intervention schools and with baseline and two follow-up data collections. Minimum sample sizes were estimated for each site based on local data and taking into account that the unit of allocation was schools and not individual students (the design effect). During the formative phase as well as within the field experiments, qualitative studies were also conducted. Discussion: The interventions were developed consistent with the Intervention Mapping approach, and the theoretical framework was based on a modified version of the Theory of Planned Behaviour. The limitations of Western social cognition models were recognized, and the theoretical framework has therefore been expanded in two directions: towards integrating cultural processes and towards taking societal factors and constraints into account. Conclusion: The project will throw light on the application of social cognition models as well as the usefulness of the Intervention Mapping approach to intervention development in sub-Saharan Africa.