The effect of high doses of omeprazole on the proliferation of the histamine-storing endocrine cells in the oxyntic mucosa, the so-called enterochromaffinlike (ECL) cells, was studied in the rat stomach by combining immunocytochemical staining for histamine with autoradiography after in vivo labeling with [3H]thymidine. Under basal conditions the ECL cells divided very slowly. A progressive increase in the ECL cell labeling index was observed from the second day of omeprazole treatment. The ECL cell density increased progressively from the ninth day of treatment. The plasma gastrin levels were doubled and the labeling index of the cells in the progenitor cell zone was significantly increased. Our data indicate that the omeprazole-evoked ECL cell hyperplasia is a result of accelerated self-replication. The positive correlation between the plasma gastrin concentration and the ECL cell labeling index is compatible with a causal relationship between circulating gastrin levels and increased ECL cell density.