ABSTRACT. Objective: Substance use is associated with poor mental health, but little is known regarding how use of multiple substances is associated with mental health, particularly longitudinally, in community studies. This article examines this issue in a large (N = 710), naturalhistory study of rural stimulant (cocaine and/or methamphetamine) users in three states. Method: Respondent-driven sampling recruited recent (past-30-day) stimulant users in three counties each in Arkansas, Kentucky, and Ohio. Participants were interviewed every 6 months for 3 years. Mental health was measured by the Brief Symptom Inventory, and prior 6 months' substance use was measured for 17 possible substances. Data analysis used generalized estimating equations for longitudinal data with the Global Severity Index of the Brief Symptom Inventory as the dependent variable at each interview and substance use as predictor variables measured by number of substances used in the past 6 months and, separately, the 17 individual substances, adjusting for use of substanceuse treatment, demographics, and recruitment site. Results: On average, both Global Severity Index score and use of many substances declined over the course of study. Global Severity Index score was signifi cantly associated with (a) greater number of substances used in the past 6 months (p < .0001) and (b) use of crack cocaine, methamphetamine, and nonprescription use of prescription painkillers and tranquilizers. Conclusions: Multiple and specifi c substances appear to incrementally increase psychological distress. Users of cocaine and methamphetamine are present in rural areas; these associations with poor psychological health raise concerns regarding availability of local treatment services for individuals with mental-health problems, as well as substance abuse. (J. Stud. Alcohol Drugs, 71, 258-267, 2010)