This is the first report in which aspirin (ASA) has failed to inhibit aggregation of mammalian platelets. Preincubation of citrated sheep platelet rich plasma with a final concentration of 500 microM ASA for 3 minutes at 37 degrees C did not inhibit aggregation induced by either arachidonic acid (AA; 1.6 mM), ADP (2.5 microM), collagen (5.6 micrograms/ml) or thrombin (0.04U). Instead, ASA potentiated the aggregation response produced by these agents except AA. Platelet aggregation that was reversible with ADP became irreversible after adding ASA. The inhibitory properties of ASA was confirmed with human platelets, challenged with AA, ADP, adrenalin and collagen. These findings suggest that sheep platelets have an ASA resistant cyclo oxygenase and may be able to aggregate by a pathway that is independent of arachidonic acid.