Depression affects approximately 18.8 million adults annually. In patients recovering from coronary artery bypass graft (CABG) surgery, high rates of depression have been reported and depression is associated with increased morbidity and mortality. Recent discoveries show that depression involves changes in proinflammatory cytokines and inflammatory markers that are also implicated in progressive coronary artery disease (CAD) and its complications. This proposed research is based on the hypothesis that the proinflammatory cytokine network is one physiological system that mediates depression with possible clinical significance for CABG patients. It builds upon a conceptual model linking depression, Proinflammatory cytokines, inflammatory markers, and upon initial work regarding the efficacy of cognitive behavioral therapy (CBT) in CABG patients. CBT is a structured intervention based on identification and reframing of negative thoughts that has substantially reduced the incidence of major depression in pilot studies. In this study, the biological mechanisms of CBT will be evaluated by testing its effects on proinflammatory cytokines (interleukin [IL]-6 and its soluble receptor [slL-6r]) and inflammation markers (C-reactive protein [CRP] and soluble intercellular adhesion molecule a [slCAM-1]). CABG patients are an ideal population in which to examine the biological mechanisms of CBT because 1) the procedure is so pervasive, 2) rates of postoperative depression are high, 3) depression is associated with poorer clinical outcomes, and 4) progressive CAD is the major cause of morbidity and mortality in these patients. The aims of the study are to evaluate the effects of CBT on the indicated biological markers, evaluate the temporal correlations between depressive symptoms and biological markers in patients receiving CBT, and describe the relationship of changes in depressive symptoms to changes in biological markers and treatment. A 2-group randomized experimental pretest-posttest design is proposed. After screening, 114 patients with major depression will be randomized to usual nursing and medical care or 8 weeks of nurse-led CBT plus usual care. Blood sampling will occur 1 month and 3 months after hospital discharge. Data will be analyzed using hierarchical linear models and stepwise linear regression, controlling for the effects of demographic and clinical variables including age, gender antidepressant use, statin use, and cardiopulmonary bypass time.