Background: Alcohol-related injuries, particularly motor vehicle, are an important cause of adolescent mortality. School-based alcohol prevention programs have not been evaluated in terms of driving outcomes. This study examined the effects on subsequent driving of a high school-based alcohol prevention program. Methods: The Alcohol Misuse Prevention Study included a randomized test of the effectiveness of an alcohol misuse prevention curriculum conducted among 4635 10th-grade students. Students were assigned to intervention (n = 1820) or control (n = 2815) groups and were followed for an average of 7.6 years after licensure, which typically occurred during or shortly after 10th grade. Outcomes examined included alcohol-related and other serious offenses, and at-fault, single-vehicle, and alcohol-related crashes. Results: Only serious offenses (which included alcohol-related) had a significant treatment effect (statistically marginal) after we adjusted for sex, age, race, alcohol use/misuse, family structure, presence of prelicense offenses, age of driver licensure, and parental attitudes toward teen drinking. The effect was found only during the first year of licensure (estimated adjusted relative risk = 0.80, confidence interval = 0.63-1.01). Two first-year serious offense interactions were found. The positive effect was strongest among the largest subgroup of students, those who were drinking less than one drink per week on average before the curriculum, compared with those who drank more than one drink per week (p = 0.009). The effect was also stronger for the small subgroup of students whose parents had not expressed disapproval of teens' drinking, compared with those whose parents had disapproved (p = 0.004). Conclusions: These findings suggest that a high school-based alcohol prevention program can positively affect subsequent driving, particularly that of students who do not use alcohol regularly. The results highlight the need to start prevention efforts early and extend them beyond the initial exposure to driving. Programs should incorporate the differing backgrounds of the students. (C) 2001 Lippincott Williams & Wilkins, Inc.