Valdecoxib is a second generation selective COX-2 inhibitor that can induce cell apoptosis in a variety of cell types, but its precise regulatory mechanism is unknown. Apoptosis of Eca109 cells and p38 mRNA expression were investigted. The expression of p-p38MAPK, Fas and FasL proteins were detected by immunohistochemical staining and FCM. Valdecoxib increased the apoptosis rate of Eca109 cells. Fas and FasL protein expression was up-regulated in the valdecoxib groups, while SB203580 partly inhibited the valdecoxib-induced overexpression. Valdecoxib increased p38MAPK expression, while SB203580 inhibited the overexpression of this protein and the apoptosis rate decreased. The expression of Fas, FasL and p38MAPK protein were positively correlated with the apoptotic rate. In conclusion, valdecoxib activates the p38MAPK pathway, thus up-regulating expression of the Fas and FasL proteins, which may be one of the mechanisms through which valdecoxib induces apoptosis.