Proton pump inhibitors and H2-receptor antagonists suppress gastric acid secretion and secondarily induce hypergastrinemia. Sustained hypergastrinemia has a trophic effect on stomach fundic mucosa, including enterochromaffin-like (ECL) cell hypertrophy and hyperplasia. Histomorphometric quantitation of the pharmacologic gastric effects was conducted on 10 male and 10 female rats treated orally with LY307640 sodium, a proton pump inhibitor, at daily doses of 25, 60, 130, or 300 mg/kg for 3 mo. Histologic sections of glandular stomach, stained for chromogranin A, were evaluated by image analysis to determine stomach mucosal thickness, mucosal and nonmucosal (submucosa and muscularis) area, gastric glandular area, ECL cell number/area and cross-sectional area. Total mucosal and nonmucosal tissue volumes per animal were derived from glandular stomach volumetric and area data. Daily oral doses of compound LY307640 sodium caused slight to moderate dose-related mucosal hypertrophy and ECL cell hypertrophy and hyperplasia in all treatment groups as compared with controls. All observed effects were prominent in both sexes but were generally greater in females. The morphometric sampling schemes were explored to optimize the data collection efficiency for future studies. A comparison between the sampling schemes used in this study and alternative schemes was conducted by estimating the probability of detecting a specific percentage of change between the male control and high-dose groups based on Tukey's trend test. The sampling scheme analysis indicated that mucosal thickness and mass had been oversampled. ECL cell density quantitation efficiency would have been increased by sampling the basal mucosa only for short-term studies. The ECL cell size sampling scheme was deemed appropriate for this type of study.