The prostaglandin H synthase-2 selective non-steroidal antiinflammatory drugs nimesulide, NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide), flosulide and SC 58125 (5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H- pyrazole) as well as the non-selective non-steroidal antiinflammatory drugs indomethacin, meclofenamate and ibuprofen were compared in a WISH (human amnionic epithelial cell) cellular assay of prostaglandin H synthase-2 activity. Varying amounts of prostaglandin E2 were induced in WISH cells using either interleukin-1beta, tumor necrosis factor-alpha or phorbol 12-myristate 13-acetate, alone or in combination, or with okadaic acid as stimulants. The results from these studies demonstrated that under conditions which generate greater amounts of prostaglandin E2, the potency of both prostaglandin H synthase-2 selective and non-selective non-steroidal antiinflammatory drugs may be reduced. Dexamethasone, a transcriptional inhibitor of prostaglandin H synthase-2, also became progressively less effective in cells activated by combinations of stimuli or with okadaic acid. We conclude that decreases in potency under conditions of high levels of prostaglandin H synthase-2 expression and prostaglandin E2 production are observed equally with prostaglandin H synthase-2 selective and non-selective inhibitors.