The effects of long-term treatment with omeprazole on the gastric mucosal morphology was studied. Eighty male Sprague-Dawley rats were used and divided into 4 equal groups. Half of the animals in 3 of the groups were given omeprazole, 40 mumol/kg body weight, orally once daily for 130 days. The remaining rats in these groups served as controls. Half of the rats in the fourth group were given subcutaneous injections with pentagastrin, this group received vehicle only. At the end of the treatment period, all animals were killed by vascular perfusion with fixative and the gastric corpus mucosae prepared for light and electron microscopy. Quantitative morphometry was used to evaluate eventual effects of treatment on the different epithelial cell types which are present in the corpus mucosa. Omeprazole treatment resulted in an increased mucosal thickness as a result of a proportional increase in all types of epithelial cells with the exception of the endocrine cells. These cells increased in number by 100%. A similar increase was seen after pentagastrin treatment. In the omeprazole-treated rats, there was also an increase in the size and number of pepsinogen granules within the zymogen cells. All changes in gastric mucosal morphology seen after 130 days of treatment with omeprazole turned out to be reversible and were not seen after a recovery period of 3 months.