The temporal effect of (R)-α-methylhistamine on epithelial cell proliferation throughout the rat gastrointestinal tract was investigated. (R)-α-methylhistamine was administered at 100 mg/kg orally and the rats were sacrificed 1, 24, 48, 72 and 144 h later. All the animals received 5-bromo-2′-deoxyuridine, (BrdU), 200 mg/kg i.p., 2 h before sacrifice. Gastrointestinal tissue was processed for histology and immunohistochemistry. (R)-α-methylhistamine caused a progressive increase in mucosal thickness of gastric fundus, distal small intestine and distal colon. Statistically significant differences from control values were found between 48 and 72 h after (R)-α-methylhistamine. (R)-α-methylhistamine significantly increased the number of BrdU-positive cells in the gastric fundus and antrum, intermediate and distal small intestine and distal colon. Peak effects were observed between 1 and 24 h after (R)-α-methylhistamine administration. Proliferating cell number and mucosal thickness were comparable to those of control rats at 144 h. (R)-α-methylhistamine exerts a long lasting growth-promoting effect on the stomach, distal small intestine and distal colon. Present data support a role of histamine H3 receptors in the normal regulation of cell cycle in epithelial tissue.