This study evaluates the impact of the African Youth Alliance (AYA) program on the sexual behavior of young people aged 17–22 in Uganda. Between 2000 and 2005, the comprehensive multicomponent AYA program implemented behavior-change communication and youth-friendly clinical services, and it coordinated policy and advocacy. The program provided institutional capacity building and established coordination mechanisms between agencies that implemented programs for young people. The analysis of findings from both a self-reported exposure design and a static group comparison design indicated that AYA had a positive impact on sexual behavior among young females but not among young males. AYA-exposed girls were at least 13 percentage points more likely to report having used a condom at last sex, at least 10 percentage points more likely to report that they had consistently used condoms with their current partner, at least 10 percentage points more likely to have used contraceptives at last sex, and 13 percentage points more likely to have had fewer sex partners during the past 12 months, compared with girls who were not exposed to the AYA program. Scaling up the AYA program in Uganda could, therefore, be expected to improve significantly the sexual and reproductive health of young women. Effective strategies for promoting safer sexual behaviors among boys and young men must be identified, however.