This exploratory study examines differences in the prevalence of drug use by gender among twelfth grade students (n = 464) in selected rural and suburban high schools in west-central Ohio. The lifetime use of alcohol and other drugs is common among all groups. Proportionally fewer boys in rural schools than boys in suburban schools reported the use of marijuana, inhalants, and LSD, or recent episodes of drunkenness. No statistically significant differences emerged between girls in rural and, suburban schools. Afterschool employment practices may help explain the observed differences.