The antagonistic effect of salicylic acid (SA), the major metabolite of aspirin, on aspirin (ASA)-induced inhibition of cyclooxygenase has been recognized in vivo and in vitro. Salicylamide is available with aspirin in some analgesic preparations. Salicylamide shares important characteristics with salicylic acid including the lack of effect on cyclooxygenase and platelet aggregation as well as a close structural resemblance. This prompted us to study the interaction of salicylamide with aspirin and/or SA on rat platelet and cyclooxygenase. Our results showed that salicylamide has, unlike SA, no blocking effect on the anticyclooxygenase effect of aspirin in vitro. Moreover, salicylamide could dose-dependently prevent the aspirin-blocking effect of SA on platelet cyclooxygenase. These results suggest that salicylamide and SA compete for a receptor on cyclooxygenase different to that of aspirin. A functional model of cyclooxygenase enzyme is proposed.