Little is known about the association of depression subtypes with inflammatory markers predictive of coronary artery disease. In a sample of younger adults representative of the U.S. population, we examined differences in serum C-reactive protein (CRP) among individuals with atypical major depressive disorder (MDD; n = 16), nonatypical MDD (n = 93), and no MDD (n = 1,682). Adults with atypical MDD exhibited higher CRP levels than those with no MDD (mean difference = 1.56 mg/L) or nonatypical MDD (mean difference = 1.40 mg/L), even after adjustment for potential cofounders, anxiety disorders, body mass, and smoking. Nearly twice as many adults with atypical MDD had CRP levels in the high cardiovascular risk range than did those with no MDD or nonatypical MDD. CRP levels of adults with nonatypical MDD or no MDD did not differ. Individuals with atypical depression may be partially driving the overall depression-inflammation relationship and may be a subgroup at elevated risk for coronary artery disease.