Depression is frequently seen in patients following myocardial infarction (MI), many of whom are receiving digitalis glycosides, beta-blockers, or other agents that may exert central nervous system (CNS) effects. In a prospective study of the clinical significance of post-MI depression, 335 patients were assessed using a standardized diagnostic interview for depression at 8 to 10 days, and 190 were reinterviewed at 3 to 4 months. Patients prescribed digitalis, beta-blockers, or other cardioactive medications at hospital discharge were identified. Logistic regression analyses were performed to determine the contribution of these agents to depression at 3 to 4 months, controlling for medical and sociodemographic factors as well as for baseline depression. Treatment with digitalis predicted depression at 3 to 4 months (p less than 0.05); no other medications, including beta-blockers, predicted depression (p greater than 0.10). Digitalis may have CNS effects that contribute to depression post-MI and this finding should be considered in the differential diagnosis of depression in cardiac patients.