The HeadOn program not only significantly increased participants' substance abuse prevention-related knowledge and decreased their rates of substance-taking behavior, it also changed the balance between risk and protective factors for substance abuse, such that protective factors increased and risk factors decreased postintervention. Findings of the feedback sessions with youth showed that the HeadOn substance abuse prevention program was acceptable to them and produced marked increases in accurate knowledge about substance abuse prevention compared to the Life Skills Training Program. HeadOn produced significantly high levels of accuracy in objective knowledge about drug abuse prevention. This was likely due to the fluency-based computer-assisted instruction feature of the program, which promotes mastery and long-term retention of the material presented. Students in the HeadOn group generally reported significantly higher baseline levels of substance use and intentions to use substances compared to the Life Skills group. The cost analysis showed that HeadOn produced slightly greater accuracy in drug abuse knowledge related to prevention at a little more than half the cost of the Life Skills Training program. HeadOn is a self-guided program designed to deliver drug abuse scientific knowledge that will foster drug prevention attitudes and behaviors. The information imparted pertains to the various classes of drugs and their immediate and long-term physiological and behavioral effects, social skills training related to resisting drug use, and self-management skills. The evaluation involved 272 youth, 113 of whom received the HeadOn intervention and 159 of whom received the Life Skills Intervention. The evaluation consisted of a battery of questionnaires administered to participants before and after their training. 1 table, 4 figures, and 40 references