The biological mechanisms by which depression might increase risk of cardiovascular disease are not clear. Inflammation may be a key element in the development of atherosclerotic cardiovascular disease. Our objective was to determine the association between major depression and elevated C-reactive protein (CRP) level in a nationally representative cohort. We estimated the odds of elevated CRP level (>0.21 mg/mL) associated with depression in 6914 noninstitutionalized men and women (age, 18-39 years) from the Third National Health and Nutrition Examination Survey (NHANES III). The prevalence of lifetime major depression was 5.7% for men and 11.7% for women. The prevalence of elevated CRP level was 13.7% for men and 27.3% for women. A history of major depression was associated with elevated CRP level (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.20-2.24). The association between depression and CRP was much stronger among men than among women. Results were adjusted for age, African American race, body mass index, total cholesterol, log triglycerides, diabetes, systolic blood pressure, smoking status, alcohol use, estrogen use in women, aspirin use, ibuprofen use, and self-reported health status. Compared with men without a history of depression, CRP levels were higher among men who had a more recent (within 1 year) episode of depression (adjusted OR, 3.00; 95% CI, 1.39-6.48) and who had recurrent (>or=2 episodes) depression (adjusted OR, 3.55; 95% CI, 1.55-8.14). Major depression is strongly associated with increased levels of CRP among men and could help explain the increased risk of cardiovascular disease associated with depression in men.