Depression is an independent risk factor for post myocardial infarction (MI) mortality. Abnormalities in platelet function have been proposed as one of the mechanisms involved in increased cardiovascular risk among patients with depression post-MI. Depression in somatically healthy patients has been associated with increased platelet activation. Some but not all studies showed changes in blood serotonin level. Increased platelet activation and blood serotonin level have been associated with increased risk of cardiac events in patients with MI. The goal of this study was to investigate whether 1) depressed post-MI patients have higher markers of platelet activation as measured by plasma levels of beta-thromboglobulin (betaTG), platelet factor 4 (PF4) and soluble CD40 ligand (sCD40L) and higher serotonin (5-HT) levels than non-depressed post-MI patients and 2) treatment with the antidepressant mirtazapine decreases platelet activation. In this study, 25 depressed post-MI patients were asked for blood collection before start as well as after 8 weeks treatment with mirtazapine or placebo. The control group (n=22) consisted of non-depressed post-MI patients, matched for age, gender and time elapsed since MI. Plasma levels of betaTG, PF4 and sCD40L were not statistically different between the groups, but 5-HT levels were significantly higher in depressed patients. Treatment with mirtazapine resulted in a non-significant decrease in betaTG and PF4 and platelet 5-HT levels. Platelet and whole blood 5-HT, but not platelet activation was significantly increased in depressed post-MI patients. Treatment with mirtazapine showed a non-significant decrease in platelet activation and platelet 5-HT.