The cardiovascular effects of tricyclic antidepressants (TCAs), including the propensity of these agents to be fatal in overdose, have been well described. It has been established further that even at therapeutic doses the TCAs may have untoward cardiovascular effects in the context of underlying ischemic heart disease. By comparison, the selective serotonin reuptake inhibitors (SSRIs) as a class are less likely to affect cardiovascular parameters in depressed patients who are otherwise healthy. Importantly, the SSRIs in overdose situations are enormously safer than TCAs and rarely have been associated with cardiotoxic effects when ingested alone. More recently, the safety and efficacy of several of the SSRIs have been evaluated in patients with existing ischemic heart disease. Although the studies have involved a limited number of patients, the available data suggest that SSRIs are not associated with adverse cardiovascular effects in these patients and are safer than TCAs in the treatment of depression in patients with heart disease. The prevalence of cardiovascular disease and the evidence that comorbid depression with cardiovascular disease (for example, following myocardial infarction) increases the risk of mortality underscore the importance of understanding the cardiac effects of antidepressants and the need for effective antidepressants that are free of adverse cardiovascular effects. At present, the SSRIs should be considered first-line agents for the treatment of depressed patients with cardiovascular illness, particularly ischemic heart disease. Among the SSRIs, those with a lower potential for causing pharmacokinetic drug interactions generally are preferred.