Previous studies have shown that apoptosis of neutrophils represents a physiologic clearance mechanism in the circulation and in the tissue to create and maintain homeostasis of neutrophil numbers. It is well known that spontaneous and Fas-mediated apoptosis of neutrophils can be regulated by proinflammatory mediators. The effects of a selective cyclooxygenase-2 (COX-2) inhibitor, NS-398, on the Fas-mediated apoptosis in inflammatory stimuli-activated neutrophils were examined. Tumor necrosis factor-α(TNF-α) and granulocyte-macrophage stimulating factor (GM-CSF) enhanced PGE2 release through induction of COX-2, but not interleukin-1β(IL-1β) and IL-8. TNF-α- and GM-CSF-induced PGE2 release was abolished by the addition of NS-398 (1 μM), nevertheless NS-398 did not change the TNF-α- and GM-CSF-induced expression of COX-2. Although not only GM-CSF but also IL-1β and IL-8 delayed Fas-mediated apoptosis in neutrophils, this effect was suppressed by the addition of NS-398 (100 μM). On the contrary, TNF-α-treated neutrophils did not change the susceptibility to Fas-mediated apoptosis. These results suggest that selective COX-2 inhibitor not only suppresses PGE2 release, but also enhances Fas-mediated apoptosis of cytokine activated-neutrophils. Recent studies have provided evidence that COX-2 inhibitor acts through a COX-2-independednt mode of various cell functions. Therefore, the proapoptotic activity of selective COX-2 inhibitor may be independent of COX-2 activity. Considering these studies, selective COX-2 inhibitor may contribute to come to an end of acute inflammation via enhanced apoptosis of neutrophils.