Depressive symptoms are associated with poor outcomes, increased risk of relapse, and high suicide rates in patients with schizophrenia and schizoaffective disorder. This randomized, open-label, parallel-group, flexible-dose study (NCT00640562) assessed the efficacy of quetiapine extended release (XR) versus risperidone on depressive symptoms in this patient population. Noninferiority of quetiapine XR versus risperidone from baseline to week 12 was assessed by least squares mean (LSM) reduction in the Calgary Depression Scale for Schizophrenia (CDSS). Noninferiority was indicated if the difference in CDSS reductions between quetiapine XR and risperidone had a 95% confidence interval (CI) lower limit of more than −2.7. Overall, 216 patients received quetiapine XR (n=109; 400–800 mg/day) or risperidone (n=107; 4–6 mg/day). In the per-protocol population, LSM CDSS reductions for quetiapine XR and risperidone were 8.4 and 6.2 points, respectively (95% CI 0.8–3.7). As the lower limit of the 95% CI was more than −2.7 and the LSM reduction for quetiapine XR was 2.2 points higher than that for risperidone, noninferiority of quetiapine XR versus risperidone was demonstrated. Adverse events for quetiapine XR and risperidone were comparable. In this study, quetiapine XR was noninferior to risperidone at reducing depressive symptoms in patients with schizophrenia or schizoaffective disorder.