The antiinflammatory agent piroxicam caused dose dependent inhibition of N-formylmethionyl-leucyl-phenylalanine (FMLP) induced monocyte superoxide release in vitro, but had no effect on the response to serum treated zymosan, phorbol myristate acetate or the calcium ionophore A23187. The inhibitory effect on the superoxide response to FMLP correlated with inhibition of specific 3H-FMLP binding. Piroxicam did not inhibit production of leukotriene B4 stimulated either by A23187 or by FMLP with arachidonic acid. Piroxicam did not inhibit phospholipid methylation. Since piroxicam inhibited neither the superoxide response to zymosan, a membrane receptor mediated response, nor phospholipid methylation, the effect of this drug on FMLP receptor binding appears to be relatively selective. Our data also exclude a significant effect of piroxicam on activation of protein kinase C or the NADPH oxidase of mononuclear phagocytes.