Platelet activating factor, a potent inducer of in vivo platelet activation and thrombosis, has been shown to be excessively active in acute ischemic stroke patients. Therefore, we studied the effect of aspirin/dipyridamole therapy in inhibiting platelet activating factor-induced platelet activation in acute ischemic stroke patients, 23 taking aspirin/dipyridamole and 21 untreated. Aspirin/dipyridamole-treated patients failed to show suppression of platelet activating factor-induced platelet aggregation even though collagen-induced activation was inhibited, suggesting that platelet activating factor acts by cyclooxygenase-independent mechanisms. Failure to suppress cyclooxygenase-independent mechanisms of platelet activation may explain the limited usefulness of current antiplatelet therapy, aspirin in particular, in stroke prevention. The role of selective platelet activating factor antagonists both in isolation and combined with aspirin needs to be investigated for their usefulness in the treatment and prevention of ischemic stroke.