The evaluation of the Department of Educations’ life skills program on HIV and AIDS prevention among Grade 9 students in 22 randomly allocated schools in KwaZulu-Natal, South Africa, showed only a significant increase in student knowledge about HIV/AIDS in the intervention group compared with the control group. No effects were found on safe sex practices (condom use, sexual intercourse) or on measures of psychosocial determinants of these practices (attitude and self-efficacy). A process evaluation among the teachers showed that some implemented the program fully (seven schools) and some partially (four schools). An exploratory analysis showed that students who received the full intervention were more positive in their perceptions about sexual behavior and social connectedness (at 10-month follow-up) and reported less sex and more condom use (at 6-month follow-up) than students in the partial and control groups. These limited effects therefore call for further analysis of the content and implementation strategies used in the classroom.