Background and Aims: Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it was reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy, using gastrin transgenic mice. Materials and Methods: Hypergastrinemic mice (ACT-GAS mice) received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from five weeks of age and were killed at 16 or 24 weeks. Some ACT-GAS mice received celecoxib from 16 weeks and were killed at 24 weeks. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and prostaglandin E₂ (PGE₂) levels were evaluated. Results: All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-week-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in the interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE₂ levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE₂ levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. Conclusion: COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.