This study was designed to compare the effects of omeprazole and cimetidine on ultrastructural changes in parietal cells of guinea pigs during histamine stimulation. Both omeprazole and cimetidine remarkably inhibited acid secretion induced by histamine stimulation. Omeprazole, however, failed to prevent the morphological transition of parietal cells to an active stage during histamine stimulation, in contrast to cimetidine which inhibited the morphological transition. In addition, it was noticed that administration of omeprazole caused vacuolation in approximately 27% of all parietal cells. This phenomenon was not seen in control animals with histamine stimulation alone and only very rarely in cimetidine treated animals. Ultrastructural findings suggested that vacuoles originated in secretory canaliculi of parietal cells. These results may be the key to explain the difference of the inhibitory mechanism between omeprazole which acts on the final step of intracellular process (so-called proton pump) and cimetidine which acts on the H2-receptor site of plasma membrane.