The over-expression of COX-2 (Cyclooxygenase 2) protein has been reported to play a key role in the incidence and development of Helicobacter pylori-associated gastric cancer. The induction of COX-2 in the gastric cancer cells with H. pylori has been demonstrated previously, but little is known about the mechanism. This study reported that the COX-2 mRNA and proteins expression level and the activity of COX-2 promoter increased remarkably with H. pylori stimulation in the MKN45 gastric cancer cells. H. pylori also stimulated phosphorylation of p38MAPK and ATF-2, which is the downstream kinase of p38MAPK. Moreover, the expression levels of COX-2 were suppressed with p38MAPK inhibitor treatment. These results suggest that H. pylori-induced activation of p38MAPK/ATF-2-mediated signal pathway is necessary for the expression of COX-2.