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The study purpose was to examine differences in substance use among individuals in drug court (N = 583) in rural Appalachian (n = 301) and urban non-Appalachian areas (n = 282). A series of logistic regression analyses suggested individuals in the rural Appalachian area were significantly more likely to report lifetime use of cocaine, illicit opiates, and illicit benzodiazepines, but they were less likely to report methamphetamine use when compared with individuals in the urban non-Appalachian area. Regarding past 30-day use, a series of logistic regression analyses suggested individuals in the rural Appalachian area were significantly more likely to use marijuana, illicit opiates, and illicit benzodiazepines, but they were less likely to report crack cocaine use when compared with individuals in the urban non-Appalachian area. Identifying differences which exist in substance use is the first step in generating evidence-based structural changes in treatment drug court programs. Future research should focus on better understanding context in terms of demographic, geographic, and economic conditions, which may be of critical influence on substance use and treatment planning.