Protecting You/Protecting Me (PY/PM) is a classroom-based, alcohol-use prevention and vehicle safety program for students in grades 1–5 developed by Mothers Against Drunk Driving (MADD). PY/PM is one of the first alcohol prevention programs targeting children that incorporates emerging research on the adverse effects of alcohol on the developing brain. In this study, we surveyed fifth grade students, some of whom were exposed to their fifth consecutive year of PY/PM implementation. Results indicate that, relative to comparison students from matched schools, PY/PM students increased their knowledge of the effects of alcohol on the developing brain, their perception of the potential harm of alcohol use, and their vehicle safety skills. PY/PM students also exhibited increased negative attitudes toward underage drinking, increased their intentions not to use alcohol, and reported decreased riding with an impaired driver. PY/PM did not have an effect on alcohol use per se of these fifth graders. Path modeling revealed that knowledge of the effects of alcohol on the developing brain had both a direct and an indirect effect on alcohol use, the latter by increasing perceptions of the harm of underage alcohol use which, in turn affected intentions to use and use itself. Teaching children about the effects of alcohol on the developing brain appears to be a promising strategy for underage alcohol use prevention.