Objective: Depression and low social support are risk factors for medical morbidity and mortality after acute MI. The ENRICHD study is a multicenter, randomized, controlled clinical trial of a cognitive-behavioral treatment for depression and low social support in post-MI patients. A total of 2481 patients were recruited (26% with low social support, 39% with depression, and 34% with low social support and depression). Our objective is to describe the rationale, design, and delivery of the ENRICHD intervention. Methods: Key features of the intervention include the integration of cognitive-behavioral and social learning approaches to the treatment of depression and a diverse set of problems that can contribute to low social support; rapid initiation of treatment after MI; a combination of individual and group modalities; adjunctive pharmacotherapy for severe or intractable depression; training, certification, and supervision of therapists; and quality assurance procedures. Results: The trial's psychosocial and medical outcomes will be presented in future reports. Conclusions: The ENRICHD protocol targets two complex psychosocial risk factors with a multifaceted intervention, which is delivered in an individualized manner to accommodate a demographically, medically, and psychiatrically diverse patient population. Additional research will be needed to identify optimal matches between patient characteristics and specific components of the intervention.