Repeated intraperitoneal administration of compound 48/80 to rats produced gastric lesions, a decrease in connective tissue mast cells (CTMCs) and an increase in gastric mucosal mast cells (MMCs). The ratio of MMC to CTMC was significantly correlated with lesion formation. A mast cell stabilizer, MAR-99 (50 mg/kg), prevented lesion formation and changes in the mast cells. Omeprazole (20 or 60 mg/kg) significantly reduced the gastric lesions, but mast cell changes persisted. Cimetidine (50 mg/kg) could not inhibit compound 48/80-induced lesions nor a decrease in CTMCs, but did prevent an increase in MMCs. These facts suggest that in compound 48/80-induced gastric lesions chemical mediators released from CTMCs might be trigger factors, while intraluminal gastric acid might be an aggravating factor. Furthermore, the increase in MMCs might be regulated by histamine released from the CTMCs via H2 receptors and have no causal relation to lesions formation.