This study investigated the effects of antidepressant treatment on platelet activation in depressed patients with ischemic heart disease (IHD). Plasma levels of platelet α-granule release products β-thromboglobulin (BTG) and platelet factor 4 (PF4) were measured in 17 depressed patients with IHD who were treated in a 6-week, double-blind trial with either paroxetine (10 patients) or nortriptyline (7 patients). Baseline measurements of BTG and PF4 were significantly elevated in both drug treatment groups before the initiation of antidepressant therapy compared with those of healthy control subjects. In the paroxetine group, mean PF4 and BTG levels significantly decreased from these elevated baseline values within 1 week of treatment and remained low at 3- and 6-week measurements. In contrast, the nortriptyline group did not exhibit a significant decrease in PF4 or BTG plasma levels after 1, 3, or 6 weeks of treatment. Therefore, platelet activation in depressed patients with IHD seems to be inhibited by the selective serotonin reuptake inhibitor paroxetine. The effect of paroxetine on PF4 and BTG plasma levels suggests that it may reduce platelet aggregation in vivo and may positively impact IHD-related mortality in this population.