In sub-Saharan Africa, theory and evidenced-based interventions that are systematically designed and using sound evaluation methods to report on effectiveness are limited. A sex education programme called SPEEK was developed, implemented and evaluated in Ghana using the Intervention Mapping approach. SPEEK aimed at delaying sexual initiation, reducing sexually transmitted infections (STIs) and preventing pregnancy, targeting junior high school students in a West African rural setting. The final programme included 11 (interactive) lessons using a diverse range of theory-based methods. In this article, we report on the effect evaluation of the programme. Participating schools were randomized to the intervention (N = 10 schools) and a waiting-list control group (N = 11 schools). The students completed survey questionnaires at baseline (N = 1822), at direct post-test (N = 1805) and at six months follow-up (N = 1959), measuring cognitive and affective psychosocial determinants of sexual delay, condom use and STI testing. Mixed regression models showed that at direct post-test, students having received the SPEEK programme scored significantly more positively on knowledge on condom use, pregnancy and STIs testing; attitude toward exercising sexual rights, condom availability and condom use; perceived behavioural control toward sexual delay, condom use and sexual intercourse; and perceived risk toward STIs (P’s < 0.002). The results suggest that the programme may improve adolescent sexual health in Ghana or in similar cultures, but would need further study that include behavioural measures and a longer follow-up to make this assertion with more confidence.