Young to middle-aged women usually have notably lower rates of cardiovascular disease (CVD) than their male counterparts, but African American women lack this advantage. Their elevated CVD may be influenced by sex differences in associations between depressed mood and CVD risk factors. This cross-sectional study examined whether relations between scores on the Center for Epidemiologic Studies-Depression (CES-D) scale and a spectrum of CVD risk factors varied by sex among African Americans (n = 1076; ages 30-64) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Sex-stratified multiple regressions and logistic regressions were conducted. Among women, CES-D scores correlated positively with systolic blood pressure and waist-to-hip ratio (P's < .05), but inversely with high-density lipoprotein cholesterol (HDL-C) (P < .01). Women had twice the odds for metabolic syndrome if CES-D scores ≥16 and had a ≥14% increase in odds of hypertension, abdominal obesity, and low HDL-C with each 5-unit increase in CES-D scores. Among men, CES-D scores correlated positively with high-sensitivity C-reactive protein (P < .05), and odds of hypertension increased by 21% with each 5-unit increase in CES-D scores. Depressive symptoms may promote premature CVD risk in African Americans, at least in part, via CVD risk factors and prevalent metabolic syndrome, particularly in African American women.