Objective: To investigate the influence of COX-2 specific inhibitor NS-398 on growth of pancreatic cancer and its mechanism. Methods: The expressions of COX-2 and VEGF in different human pancreatic cancer cell lines (BxPC-3, SWl990, Capan-2, Aspc-1, PANC-1) were determined by qRT-PCR and Western blot respectively, and the inhibitory effects of NS-398 on proliferation of each pancreatic cancer cell line in vitro were measured by MTT assay. Orthotopic transplantation models of pancreatic cancer using the most sensitive cell line identified by in vitro tests were established in nude mice, and then the tumor-bearing mice were randomly divided into experimental group and control group, which underwent treatment with NS-398 or normal saline respectively. The growths of the tumor xenografts in the two groups were compared and the expressions of COX-2 and VEGF protein as well as microvessel density (MVD) in the tumor tissues were detected. Results: All the pancreatic cancer cell lines presented COX-2 and VEGF expressions with varying degrees; NS-398 inhibited the in vitro proliferation of all the pancreatic cancer cells in time- and concentration-dependent manner, and among them, Bxpc-3 cells had the highest expression levels of COX-2 and VEGF, and were also most sensitive to NS-398. After establishment of orthotopic pancreatic cancer model with Bxpc-3 cells, in mice in experimental group compared with those in control group, the average tumor volume was significantly reduced (20.215 2 mm3 vs. 204.444 4 mm3), and the expression levels of COX-2 and VEGF as well as MVD were all significantly reduced (all P<0.05). Conclusion: NS-398 has inhibitory effect on growth of pancreatic cancer, and the mechanism may be related to its decreasing VEGF gene expression via COX-2 pathway and thereby reducing tumor angiogenesis.