Objectives: The primary objective was to compare the efficacy and tolerability of quetiapine and risperidone in the treatment of mood symptoms, drug cravings, and drug use in outpatients with concurrent DSM-IV-defined bipolar I or II disorder and cocaine or methamphetamine dependence. Method: Men and women of all ethnic origins, 20 to 50 years of age, were eligible to participate. Persons were excluded if they were inpatients, met DSM-IV criteria for substance-induced mood disorder, had any other substance dependence, were euthymic or suicidal, had any life-threatening illnesses, or were currently receiving antipsychotic medications. Duration of the trial was 20 weeks. Study participants attended weekly visits and were evaluated for mood symptoms, drug cravings, drug use, and medication side effects. Treatment outcomes were analyzed using linear mixed models. Fixed-effects terms for medication group, study week, and group-by-study-week were included in the models. The study was conducted between October 2002 and November 2006. Results: Of 124 consenting outpatients, an evaluable sample of 80 patients who attended baseline and at least 1 follow-up study visit was formed. The mean ± SD exit dose for quetiapine was 303.6 ± 151.9 mg/day and 3.1 ± 1.2 mg/day for risperidone. Both quetiapine (N = 42) and risperidone (N = 38) significantly improved manic and depressive symptoms and reduced drug cravings (p < .0005) compared to baseline. Decreased drug cravings were related to less frequent drug use (p = .03). The 2 medications did not significantly differ in their effects on mood symptoms, drug craving, or drug use. Conclusions: Relative to baseline mood and drug-craving status, both quetiapine and risperidone were associated with manic, mixed, and depressive symptom improvement and reduced drug cravings. Both medications were well tolerated. The interpretation of these results is limited by the absence of a placebo control. Trial Registration: clinicaltrials.gov Identifier: NCT00227123. © Copyright 2008 Physicians Postgraduate Press, Inc.