OBJECTIVE To elucidate the mechanism of action of a wide range of non-steroidal anti-inflammatory drugs (NSAIDs) on the respiratory burst of isolated normal PMNs in buffered saline and plasma. METHODS The oxidative burst of PMN was assessed by luminol enhanced chemiluminescence and myeloperoxidase-mediated iodination. Cells were stimulated by the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), serum coated zymosan or the phorbol ester phorbol myristate acetate (PMA). RESULTS When using buffered saline as the suspending medium, tenoxicam, piroxicam, ibuprofen, ketoprofen and diclofenac, at concentrations achieved clinically, inhibited both PMA- and FMLP-induced luminol chemiluminescence. Tenoxicam and piroxicam in buffered saline also inhibited the iodination reaction. However, in plasma, which mimics the in vivo situation more closely, the inhibitory effect was markedly reduced. Only tenoxicam and piroxicam were found to cause the inhibition of luminol chemiluminescence at concentrations achieved clinically. CONCLUSIONS If these study conditions are representative of the in vivo pathological state, the results suggest that only tenoxicam, piroxicam and possibly diclofenac sodium are likely to possess anti-inflammatory properties which are independent from effects on cyclooxygenase.