The purpose of the present study was to examine the efficacy of a substance abuse-preventive intervention using CD-ROM technology among adolescents in the sixth and seventh grades (12- to 13-years-old). The CD-ROM program used interactive audio and video content to teach social resistance skills, general personal and social competence skills, and normative education. Rates of substance-use behavior attitudes, knowledge, normative expectations, and related variables were examined. From approximately 23 schools, students (n = 123) were randomly assigned to either receive the CD-ROM preventive intervention (n = 61) or to serve as a control group (n = 62). Study participants were 50% male, predominantly white (75%), and 94% came from two-parent families. Self-report data were collected using a self-administered web-based survey. Findings indicated that there were significant intervention effects on pro-drug attitudes, normative expectations for peer and adult substance use, anxiety reduction skills, and relaxation skills knowledge, with intervention students reporting improved scores on these outcomes at the posttest relative to control students. Findings indicate that a substance abuse-preventive intervention derived from an effective, school-based prevention approach is efficacious when delivered using CD-ROM technology. Research is needed to determine potential differences in the efficacy of CD-ROM prevention tools delivered in schools compared to home settings.