Little is known about which factors may adversely affect response to psychotherapy in diabetic patients with major depression. We studied the relationship of various demographic, diabetes, and depression characteristics to change in depression in 42 patients with type 2 diabetes who completed a randomized clinical trial of cognitive behavior therapy (CBT). Depression remitted in a significantly greater percentage of the patients treated with CBT than with the control intervention (85.0% vs 27.3%, p < 0.001). In the sample as a whole, nonremission of depression was associated with lower compliance with blood glucose monitoring, higher glycated hemoglobin (GHb) levels, higher weight, and a history of previous treatment for depression. In the group treated with CBT, the presence of diabetes complications and lower compliance with blood glucose monitoring were significant independent predictors of diminished response. These findings show that factors related to the medical illness, such as the presence of diabetes complications, may negatively influence the prognosis for recovery from depression. Specific coverage of these issues during psychotherapy may optimize the likelihood of treatment success in patients with diabetes.