BACKGROUND There has been little research on the treatment of depression after coronary artery bypass surgery. OBJECTIVE To test the efficacy of 2 nonpharmacological interventions for depression after coronary artery bypass surgery compared with usual care. METHODS A 12-week, randomized, single-blind clinical trial with outcome evaluations at 3, 6, and 9 months. METHODS Outpatient research clinic at Washington University School of Medicine, St Louis, Missouri. METHODS One hundred twenty-three patients who met the DSM-IV criteria for major or minor depression within 1 year after surgery. METHODS Twelve weeks of cognitive behavior therapy or supportive stress management. Approximately half of the participants were taking nonstudy antidepressant medications. METHODS Remission of depression, defined as a score of less than 7 on the 17-item Hamilton Rating Scale for Depression. RESULTS Remission of depression occurred by 3 months in a higher proportion of patients in the cognitive behavior therapy (71%) and supportive stress-management (57%) arms than in the usual care group (33%) (chi(2)(2) = 12.22, P = .002). Covariate-adjusted Hamilton scores were lower in the cognitive behavior therapy (mean [standard error], 5.5 [1.0]) and the supportive stress-management (7.8 [1.0]) arms than in the usual care arm (10.7 [1.0]) at 3 months. The differences narrowed at 6 months, but the remission rates differed again at 9 months (73%, 57%, and 35%, respectively; chi(2)(2) = 12.02, P = .003). Cognitive behavior therapy was superior to usual care at most points on secondary measures of depression, anxiety, hopelessness, stress, and quality of life. Supportive stress management was superior to usual care only on some of the measures. CONCLUSIONS Both cognitive behavior therapy and supportive stress management are efficacious for treating depression after coronary artery bypass surgery, relative to usual care. Cognitive behavior therapy had greater and more durable effects than supportive stress management on depression and several secondary psychological outcomes. BACKGROUND clinicaltrials.gov Identifier: NCT00042198.