Despite mounting evidence that depressive symptoms increase the risk of morbidity and mortality in patients who have coronary artery disease, little is known about the biologic mechanisms that underlie this association. This study examined whether depressive symptoms are associated with markers of infection and inflammation that have been implicated in the pathogenesis of coronary artery disease. Sixty-five patients who were recovering from an acute coronary syndrome were enrolled (63% men; mean age 61 years, 90% white). Depressive symptoms were assessed through self-report and observer ratings; the inflammatory molecules C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were measured in serum, as were antibody titers to 3 latent viruses associated with atherosclerosis. Patients who had more severe depressive symptoms exhibited higher levels of C-reactive protein (r = 0.27, p = 0.03) and higher rates of seropositivity to the latent viruses (r = 0.41, p = 0.001). These effects were large in magnitude: patients in the highest tertile of the depression distribution had C-reactive protein levels >50% higher than did patients in the middle and lowest tertiles; they also were 2 times as likely to show evidence of infection with all 3 latent viruses. Disparities in the extent, severity, or management of cardiac disease were not responsible for these associations. These findings provide evidence that depressive symptoms are associated with increases in C-reactive protein and pathogen burden in patients who have coronary artery disease. In doing so, they highlight a mechanism through which depressive symptoms might foster morbidity and mortality among patients who have cardiac disease.