School-based HIV prevention programmes in South African cities have been implemented to reduce new infections among adolescents. The study employed a mixed-methods approach involving quantitative surveys and qualitative interviews with students, teachers, and programme administrators. Data were collected from four cities: Johannesburg, Cape Town, Durban, and Pietermaritzburg. A significant increase in knowledge about HIV/AIDS was reported among participants in all cities, though the proportion varied (Johannesburg: 82%, Cape Town: 75%, Durban: 69%, Pietermaritzburg: 70%). School-based programmes show promise in enhancing students' knowledge but require tailored strategies to address specific urban contexts. Programmes should be adapted for local cultures and educational systems, with ongoing support from schools and communities.