OBJECTIVE Initial treatment with antidepressant medication is insufficiently effective in some patients with type 2 diabetes, and factors predicting treatment outcome are poorly understood. RESEARCH DESIGN AND METHODS Aggregate data from two published trials were analyzed to determine the rates and predictors of response to antidepressant pharmacotherapy in adults with type 2 diabetes using conventional markers of initial treatment outcome (improvement, response, partial remission, and remission). Three hundred eighty-seven patients who received up to 16 weeks of open-label, acute-phase treatment using bupropion (n = 93) or sertraline (n = 294) were studied. Logistic regression was used to identify predictors of poor treatment outcome. Candidate predictors included age, race, sex, initial Beck Depression Inventory (iBDI) score, treatment received (sertraline or bupropion), family history of depression, extant diabetes complications (eDC), and A1C level. RESULTS Of 387 patients initiated on treatment, 330 (85.3%) met criteria for improvement, 232 (59.9%) for response, 207 (53.5%) for partial remission, and 179 (46.3%) for full remission. Significant independent predictors of poor outcome included eDC (for no improvement); sertraline treatment, eDC, and younger age (for nonresponse); sertraline treatment, eDC, and higher iBDI (for failure to partially remit); and younger age and higher iBDI (for failure to fully remit). Higher pain scores predicted three of the four markers of poor outcome in the subset with pain data. CONCLUSIONS In patients with type 2 diabetes, poor initial response to antidepressant medication is predicted by multiple factors. Auxiliary treatment of pain and impairment may be required to achieve better outcomes.