This article examines prevalence of non-medical use of prescription drugs (NMUPD) in a sample of elementary and high school students in an Appalachian Tennessee county. We found that lifetime prevalence of NMUPD (35%) was higher than prevalence of cigarette use (28%) and marijuana use (17%), but lower than lifetime prevalence of alcohol use (46%). We examined characteristics, as well as risk and protective factors in several domains, as predictors of NMUPD. For comparison, we also examined these characteristics and factors as predictors of alcohol, cigarette, and marijuana use. Using survey data from a sample of late elementary school and high school students (grades 5, 7, 9, and 11), logistic regression analyses showed that the risk factors of friends' non-medical use and perceived availability, and the protective factors of preceived risk, parents' disapproval, school commitment, and community norms against youth NMUPD were significant predictors of lifetime prevalence of NMUPD. Implications for prevention are discussed.