Objectives. We assessed the effectiveness of a 5-year trial of a comprehensive school-based program designed to prevent substance use, violent behaviors, and sexual activity among elementary-school students. Methods. We used a matched-pair, cluster-randomized, controlled design, with 10 intervention schools and 10 control schools. Fifth-graders (N=1714) selfreported on lifetime substance use, violence, and voluntary sexual activity. Teachers of participant students reported on student (N=1225) substance use and violence. Results. Two-level random-effects count models (with students nested within schools) indicated that student-reported substance use (rate ratio [RR]=0.41; 90% confidence interval [CI]=0.25, 0.66) and violence (RR=0.42; 90% CI=0.24, 0.73) were significantly lower for students attending intervention schools. A 2-level random-effects binary model indicated that sexual activity was lower (odds ratio=0.24; 90% CI=0.08, 0.66) for intervention students. Teacher reports substantiated the effects seen for student-reported data. Dose-response analyses indicated that students exposed to the program for at least 3 years had significantly lower rates of all negative behaviors. Conclusions. Risk-related behaviors were substantially reduced for students who participated in the program, providing evidence that a comprehensive school-based program can have a strong beneficial effect on student behavior.