The aim is to evaluate the effects of the Competencias para adolescentes con una sexualidad saludable (COMPAS) program and compare them with an evidence-based program (¡Cuídate!) and a control group (CG). Eighteen public high schools were randomly assigned to one of the three experimental conditions. Initially, 1,563 Spanish adolescents between 14 and 16 years of age participated, and 24 months after their implementation, 635 of them completed a survey. Self-report measures collected data on sexual behavior, knowledge, attitudes, intention, sexual risk perception, and perceived norm. Compared to the CG, COMPAS increased the level of knowledge about sexually transmitted infections and improved the attitudes toward people living with human immunodeficiency virus at the 2-year follow-up. Neither intervention had a long-term impact on behavioral variables. Results suggest that COMPAS has a comparable impact to the other intervention on the variables predicting consistent condom use. Reinforcing the messages and skills that have the greatest impact on condom use and adding booster sessions following program completion as strategies to maintain long-term effects are necessary.