This study was designed to investigate ultrastructural changes in parietal cells during treatment with omeprazole. Endoscopic biopsies were performed in patients treated with omeprazole (n = 2) and cimetidine (n = 4) and in normal controls (n = 3). In the patients who received omeprazole, many parietal cells (90.9 and 66.6%) were in the "stimulated" or "partially stimulated" stage. As reported previously, our results suggest that omeprazole fails to prevent the morphological transition of parietal cells to an actively secreting phase, although it strongly inhibits acid secretion. The altered cells frequently demonstrated more marked dilation of the secretory canaliculi, compared with those of normal controls and cimetidine-treated patients. Vacuolation was found in one patient given omeprazole and one given cimetidine. In the former patient, initial famotidine treatment also led to the vacuolation of parietal cells. However, this change does not seem to imply serious parietal cell degeneration. There were no adverse morphological changes in mitochondria and nuclei in any of the groups. In conclusion, vacuolation is not specific to omeprazole. Moreover, if omeprazole is administered at a pharmacologically effective dosage for a short period of time, it may not have serious effects on the ultrastructure of human parietal cells.