Background: The proxisome prolifrator-activated receptor gamma (PPAR ) is a member of the nuclear hormone receptor superfamily that is involved in the control of inflammation, carcinogenesis and gastric ulcer. On the other hand, the frequency of gastrointestinal ulceration is higher in cirrhotic patients compared with the normal population. The present study was designed to investigate the effect of specific PPAR ligand, pioglitazone, on the mucosal lesions induced by ethanol in cirrhotic rats and the possible involvement of nitric oxide in the pioglitazone effect. Methods: Cirrhosis was induced by surgical ligation of bile duct and sham-operated rats served as controls. Both cirrhotic and sham rats were kept for 28 days after the operation. Different groups of sham and cirrhotic animals received saline, or 5, 10 or 15 mg/kg pioglitazone, daily during last 5 days of the fourth week after the surgery. Another 2 groups of BDL or 2 groups of sham rats received L-NAME, a non selective inhibitor of nitric oxide synthase, alone or along with 5 mg/kg pioglitazone for 5 days. On day 28, rats were killed 1 hour after ethanol administration and the area of gastric lesions was measured. Results: The ethanol-induced gastric mucosal damage was significantly more sever in cirrhotic rats than sham-operated ones (P < 0.001). Pretreatment with pioglitazone dose dependently attenuated gastric lesions induced by ethanol in both sham and cirrhotic rats, but this effect was more significant in cirrhotic ones. Concurrent treatment of L-NAME and pioglitazone decreased the ulcer index in BDL rats more than the groups that received L-NAME or pioglitazone alone. Conclusion: We conclude that chronic treatment with pioglitazone exerts a potent gastroprotective effect on the stomach ulcers of cirrhotic rats probably due to inhibition of nitric oxide synthase.