Depressive disorders are common in patients with ischemic heart disease and have serious consequences in terms of the risk of further cardiac events and cardiac mortality. Among survivors of acute myocardial infarction, up to one fifth meet diagnostic criteria for major depression, and the presence of major depression carries a >5-fold increased risk for cardiac mortality within 6 months. This article reviews clinical trial data on the cardiac safety profiles of antidepressant agents with the aim of discussing clinical considerations in selecting the most appropriate treatment of comorbid depression in patients with ischemic heart disease. Tricyclic antidepressants are effective against depression but are associated with cardiovascular side effects including orthostatic hypotension, slowed cardiac conduction, antiarrhythmic activity, and increased heart rate. Selective serotonin reuptake inhibitors, by contrast, have benign cardiovascular profiles and are well tolerated in patients with cardiac disease. The safety of dual-acting serotonin and noradrenaline reuptake inhibitors has not been well studied. Intervention with a selective serotonin reuptake inhibitors has the potential to provide the depressed patient with ischemic heart disease relief from their depressive symptoms and may offer a potential improvement in their cardiovascular risk profile.