In recent years a large body of evidence from several longitudinal studies has emerged suggesting that depression is an independent risk factor for cardiovascular disease (CVD) and that the association between depression and increased CVD risk is not merely due to negative mood-driven behavior related with depression. Even though the underlying mechanisms are not well understood, several hypotheses and explanations have been proposed such as increased activation of the hypothalamic-pituitary-adrenal axis, abnormalities in the sympathoadrenal system, or abnormalities in platelet function. Platelet function abnormalities, including increased platelet reactivity, may predispose patients with depressive disorders to clotting diatheses and may explain their vulnerability to CVD. Serotonin secreted by platelets induces both platelet aggregation and coronary vasoconstriction. Even though serotonin itself is only a weak platelet agonist, it markedly enhances platelet reactions to a variety of other agonists. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) reduce platelet and whole blood serotonin concentrations after repeated doses, and could therefore exert an inhibitory effect on platelet activation. For that reason, it was hypothesized that SSRIs could have a protective effect against myocardial infarction (MI). Results from three currently available epidemiological studies assessing the risk of MI in patients treated with antidepressants, including SSRIs, are controversial with respect to a potential beneficial effect of SSRIs on CVD risk in depressed patients. However, there is evidence that exposure to SSRIs does not substantially increase the risk of CVD in patients. A recent randomized, double-blind, placebo-controlled, multicenter trial that evaluated the safety and efficacy of the SSRI sertraline in patients with major depression and acute MI or unstable angina suggested that sertraline is well tolerated and effective. Further epidemiological studies or longer-term clinical trials may shed more light on this issue, and answer the question conclusively, whether the effect of SSRIs on platelets or another mechanism translates into a decreased risk of CVD in depressed patients.