OBJECTIVE: Depression management in both short- and longer-term treatment studies has been associated with improvement in glycemic control. We used bupropion hydrochloride (Wellbutrin XL) to determine whether this improvement could be attributed to changes in anthropometrics or diabetes self-care. RESEARCH DESIGN AND METHODS: Ninety-three patients with type 2 diabetes and major depressive disorder (MDD) received bupropion hydrochloride in a two-phase, open-label treatment trial. Those who completed the acute phase (10 weeks; n = 75) and whose depression remitted (n = 63) continued bupropion at the remission dose and were followed in the maintenance phase (24 weeks) until attrition (n = 8) or relapse of MDD (n = 0). Self-report scales were used to measure depression symptom severity and diabetes self-care behaviors. Body composition and glycemic control were determined using dual-energy X-ray absorptiometry and serial determinations of A1C. RESULTS: BMI, total fat mass, and A1C decreased and composite diabetes self-care improved over the acute phase (-0.5 kg/m2, -0.7 kg, -0.5%, and +0.4, respectively, P < 0.01 for each), effects that persisted through the maintenance phase for BMI, A1C, and self-care (P < or = 0.01 for each). Reductions in BMI (B = 0.30, P = 0.01) and depression severity (B = 0.04, P = 0.046) independently predicted lower A1C after acute-phase treatment, whereas only reduction in depression severity (B = 0.08, P = 0.001) predicted A1C over the maintenance interval. CONCLUSIONS: In the short term, improvement in glycemic control during bupropion treatment is predicted independently by improvements in mood and body composition. Longer-term improvements in glycemic control are predicted primarily by sustained improvement in mood via mechanisms independent of anthropometric and self-care modifications.