The irreversible human platelet aggregation induced by threshold concentrations of platelet-activating factor (PAF) in citrated plasma was reversed by aspirin (100 mumol/L, with 10 minutes' preincubation). The aspirin-sensitive amplification was linked to thromboxane generation, although thromboxane could be successfully replaced by cyclic endoperoxides, as suggested by the lack of effect of dazoxiben, a selective thromboxane-synthase inhibitor. The inhibitory effect of aspirin could be overcome by using 10 times higher PAF concentrations or, even more effectively, by combining threshold concentrations of both PAF and one of the other agonists studied (ADP, epinephrine, and U-46619, a stable endoperoxide analog, but not serotonin). The irreversible response obtained in both experimental conditions could also be made reversible by the use of BW 755C or nordihydroguaiaretic acid, inhibitors of both cyclooxygenase and lipoxygenase. It is concluded that the aspirin-sensitive pathway is sufficient but not necessary to amplify the primary response of human platelets to PAF. These data may be relevant to the current debate on the efficacy of aspirin in thrombosis prevention.