Life-long administration (≥2 years) of a number of long-acting gastric acid inhibitors (including H2-receptor antagonists, omeprazole and ciprofibrate) has been associated with the development of gastric enterochromaffin-like cell (ECL cell) carcinoids in rats. It has been postulated that they are a consequence of some unique property of the longer-acting acid inhibitors. There is, however, a great deal of evidence to support the hypothesis that these gastric ECL cell carcinoids develop as a result of life-long hypergastrinaemia in rats. Several lines of investigation reported here show that gastric ECL cell hyperplasia occurs when gastrin levels are increased without the use of acid-inhibiting drugs. In rats, hypergastrinaemia developed after 4 weeks’ administration of exogenous gastrin (4 μg/kg/h). The number of gastric ECL cells per visual field had increased to 250 compared with 180 in the controls. Long-term hypergastrinaemia, induced by partial gastric corpectomy, increased plasma gastrin levels from 200 to 800 pg/ml and the density of gastric ECL cells increased from 190 to 310 cells/visual field 10 weeks after the operation. Importantly, gastric ECL cell hyperplasia, which was produced in rats by administration of omeprazole, 14 mg/kg/day for 1 year, was fully reversible following normalization of gastrin levels. Until now, gastric ECL cell carcinoids have not been reported in studies of shorter-acting, reversible H2-receptor antagonists such as ranitidine, perhaps because the correct staining techniques (i.e. Grimelius and Sevier-Munger silver stains) have not been used. We now report that in female rats, 2 years’ administration of ranitidine, 2 g/kg/ day, in the diet is associated with hypergastrinaemia and histological changes similar to those reported with omeprazole, 14 mg/kg/day, which gave the same degree of acid inhibition. Moreover, ranitidine, 2 g/kg/day, in the diet for 2 years was also associated with the development of gastric ECL cell carcinoids in 19 out of 100 rats. The results presented in this paper provide support for the hypothesis that the development of gastric ECL cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia achieved surgically or pharmacologically and is not a unique effect of any individual acid-inhibitory drug.