Zinc acexamate (ZAM) is an antiulcer agent with antisecretory and gastroprotective properties. The aim of this study was to evaluate endoscopically and morphometrically the efficacy of ZAM in the prophylaxis of gastroduodenal lesions induced by pyroxicam. Thirty nine patients from 30 to 70 years of age diagnosed with osteoarthritis without lesions in the upper digestive tract on basal endoscopy were studied. A randomized, double blind study was designed in which the patients received 20 mg/day of pyroxicam together with 300 mg/day of ZAM or placebo for 4 weeks. Clinical controls were undertaken on days 0, 14, 28 and endoscopic and histologic controls performed on days 0 and 28. The two groups were homogeneous regarding basal parameters. Endoscopic grading of the gastroduodenal lesions at the end of the study was lower in the group treated with ZAM (p < 0.001). Ulcers were found in only 2 patients (one antral and one duodenal) both of whom were in the placebo group (10.5%). Histologic scoring following treatment demonstrated higher values in the placebo group (p < 0.001) and scarce alterations with respect to base values in the group treated with ZAM. Morphometric quantification showed lower cell densities in both groups at the body level (p < 0.001). However, these did not vary in the antrum in the group treated with ZAM but increased in the placebo group (p < 0.001) as an expression of proliferative cell response to mucosal damage. At a single nightly dosis of 300 mg ZAM is effective in the prophylaxis of gastric and duodenal lesions induced by pyroxicam.