The objective of this study was to evaluate the efficacy and safety of olanzapine in patients with schizophrenia and comorbid substance abuse disorders. Thirty patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder as well as criteria for substance abuse or substance dependence, were treated in a 12-month prospective, open-label trial of olanzapine. Patients were evaluated with multiple efficacy and safety measures at baseline and then monthly thereafter. Statistically significant improvement was noted in psychopathology, levels of hope, and safety measures. Seventy percent (n = 21) of the patients achieved early full substance abuse remission at the end of the study period, while 30% (n = 9) achieved early partial substance abuse remission. Our results indicate that olanzapine treatment improved psychopathology, increased hopefulness, and reduced antipsychotic-associated side effects. The benefits observed with olanzapine treatment may contribute to the patients' substance abuse remission.