Psychosocial factors, particularly depression and lack of social support, are important predictors of morbidity and mortality in patients with coronary heart disease. This article describes the design and methods of the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) study, a multicenter, randomized clinical trial involving 3000 patients enrolled after acute myocardial infarction. ENRICHD aims to investigate the effects of a psychosocial intervention that targets depression and/or low social support on survival and reinfarction among adult men and women who are at high risk for recurrent cardiac events because of psychosocial factors (depressive or social isolation). Design features include the use of an individually tailored yet standardized intervention, rigorous clinical trial methods, and enrollment of a large number of women and minorities.