To study whether chemically induced cytotoxicity occurs in diabetic platelets, platelets isolated from rats made hyperglycemic (diabetic) by a prior intravenous administration of streptozotocin were incubated with menadione and the cytotoxicity was assessed by the amount of lactate dehydrogenase (LDH) released from the menadione exposed platelets as a function of time. Platelets isolated from diabetic rats released greater amount of LDH in response to menadione than those from normal rats. Consistent with this finding, induction of menadione cytotoxicity was not dependent on glutathione depletion, but on greater generation of free radicals in diabetic platelets. Greater sensitivity of diabetic platelets to the menadione-induced cytotoxicity was accompanied by release of serotonin from dense granules, suggesting that this mechanism contributes to cardiovascular diseases in diabetic subjects.