Platelet aggregation and [14C]serotonin release induced by collagen and also by ADP and thrombin were significantly decreased in patients with primary Type V hyperlipoproteinemia. Platelets derived from these patients lost their hyporesponsiveness to thrombin and ADP (but not to collagen) after washings and isolation from their plasma environment. On incubation of platelets derived from normolipidemic controls with plasma derived from patients, platelet aggregation and [14C]serotonin release were lowered by 20% and 30%, respectively. On incubation of these platelets with 100 mg/dl of chylomicron triglyceride, a 40% reduction in both platelet aggregation and [14C]serotonin release was observed. The inhibition of platelet activity was positively correlated with chylomicron concentration up to a concentration of 225 mg/dl by chylomicron triglyceride. In 2 patients, bezafibrate administration (600 mg/day) resulted in marked reduction of plasma triglyceride concentration and a parallel improvement in platelet function. The platelet hyporesponsiveness in patients with Type V hyperlipoproteinemia appears to be a consequence of platelet-chylomicron interaction. This depressed platelet function may be responsible for the absence of overt atherosclerosis noted in these patients.