OBJECTIVE: This study examined the associations of depressive symptoms with glucose concentrations and morning cortisol levels in 665 African-American and 4,216 Caucasian Vietnam-era veterans. RESEARCH DESIGN AND METHODS: Glucose level was measured as a three-level variable (diabetes, impaired glucose, and normal). Depressive symptoms were measured by the Obvious Depression Scale (OBD) from the Minnesota Multiphasic Personality Inventory. RESULTS: Regression models showed significant race x OBD interactions in relation to glucose concentration (P < 0.0001) and cortisol (P < 0.0001). The OBD was positively associated with glucose concentration and cortisol in both racial groups. However, the magnitude of those associations was larger for African Americans. Further analyses suggested that cortisol partially mediated the race difference in the relation of depressive symptoms to glucose concentrations. CONCLUSIONS: These results suggest that enhanced hypothalamic pituitary adrenal activity plays an important role in the relation of depressive symptoms to dysregulated glucose metabolism and may partially explain the differential effects of depressive symptoms on glucose levels in African-American and Caucasian male subjects.