Several factors have been related to depression for people with diabetes, but mechanisms of depression in this population remain unclear. The purpose of this research was to test mastery and self-esteem as mediators of disease-related depression in people with diabetes. A sample of 180 adults ages 21 to 81 participated in the cross-sectional, correlational study. Mastery and self-esteem mediated the relationships between depression and two predictors, effects of diabetes complications and general social support. Feelings of self-esteem alone mediated the effect of regimen demands. The effect of diabetes on daily activities had a significant, direct (i.e., nonmediated) relationship to depressive symptoms. The entire model predicted 53% of variance in depression scores (p = .0001). These findings suggest nursing strategies for managing depression in patients with diabetes.