Parietal cell morphology was studied after chronic inhibition of gastric H(+)-K(+)-adenosinetriphosphatase (ATPase) by omeprazole. Gastric mucosa from rabbits treated with omeprazole every 12 h (1 mg/kg sc) for 5 days were compared with sham-injected animals using immunohistochemistry and electron microscopy. Three immunocytochemical markers, including antibodies against the alpha- and beta-subunits of the H(+)-K(+)-ATPase, showed that some parietal cells in omeprazole-treated rabbits displayed light areas and granularity in their cytoplasm. These abnormalities were also apparent in semithin sections. Electron microscopy was used to categorize and quantitate the specific structural abnormalities in parietal cells. Cells were classified as normal, altered, or degenerated. For control tissues, altered and degenerated parietal cells were few; they collectively represented 6% of total parietal cells and were located mainly deep in the gland base. For omeprazole-treated tissues, altered and degenerated parietal cells occurred throughout the gland and averaged 62% of total parietal cells. In addition, macrophages invaded the mucosa presumably to eliminate degenerated cells. Although there was an increase in parietal cell degeneration, enhanced parietal cell generation was suggested by increases in mitosis among proliferative cells and, more specifically, in the number of preparietal cells. After 3 days of recovery from the omeprazole regimen, parietal cells and the gastric mucosa appeared to recover the normal morphology. In conclusion, blocking H(+)-K(+)-ATPase by omeprazole enhances degeneration and macrophage-mediated elimination of parietal cells and also causes an increase in preparietal cell production. Thus omeprazole temporarily changes the dynamic features of parietal cells in the rabbit to make them die early and grow fast.