The use of tobacco, alcohol, and other drugs continues to be a major public health problem in this country. Substance use/abuse prevention programs often attempt to enhance self-esteem in the hopes that improved self-esteem will give young people less motivation to use drugs and greater ability to resist pressure to use drugs. The purpose of this study was to examine the role of self-esteem in substance use; specifically to determine whether self-esteem scores differ by level of substance use, and whether scores of various aspects of self-esteem can, as a set, distinguish between users and non-users of selected substances. Participants in the study were 700 students in grades 6-12 from a single southern school district. The testing instrument was a questionnaire that included items designed to elicit demographic information, measures of self-esteem and measures of substance use. Self-esteem was measured using the Kelley Short-Form of the Hare Self-Esteem Scale. Questions dealing with substance use substance14 different measures of substance use addressing the use of tobacco, alcohol, marijuana, and other illegal drugs. Self-esteem was measured in three areas, peer, home, and school. Data were analyzed using 2 way(gender x behavior) analysis of variance for each of the 14 behaviors. For each behavior a logistic regression was conducted using the three self-esteem measures as predictor variables. Results showed significant differences between users and non-users regarding home and school self-esteem for all 14 behaviors, In each case, non-users exhibited higher self-esteem scores than users. Regarding peer self-esteem there were significant differences between users and non-users for only five of the 14 behaviors. For three of the five behaviors, users had higher scores than non-users. In addition, for two smokeless tobacco behaviors there were significant gender x behavior interactions. Results for the logistic regression analyses indicated that for males the set of self-esteem variables did distinguish between users and non-users for all 14 behaviors. Rsquare values ranged from .046 to .237. For females the set of self-esteem variables distinguished between users and non-users for 12 of the 14 behaviors (not for two smokeless tobacco behaviors). Rsquare values ranged from .057 to .218. The results indicate that self-esteem does play a role in substance use prevention and highlight the positive role that the home and school can play in substance prevention efforts.Keyword(s): health promotion, research, youth-at-risk