In view of the controversy as to whether antisecretory agents such as H2 antagonists and antimuscarinics might be cytoprotective like the PGs, the oral activity of atropine, ranitidine and PGE2 against absolute ethanol-induced lesions was evaluated in rats. The results showed that atropine and PGE2, but not ranitidine, were effective in preventing absolute ethanol-induced gastric damage. The effects were related to the doses of the ulcerogenic agent and of the cytoprotective compound. The anti-ulcer activity of atropine is considered to be an expression of cytoprotection, since the pathogenesis of ethanol-induced gastric damage was independent of gastric pH and atropine, like PGE2, does not affect basal acid secretion at a fully cytoprotective dose. Some studies were undertaken to elucidate the mechanism of gastric cytoprotection by atropine. The possibility that the anti-muscarinic agent might work as a mild irritant was ruled out since, like PGE2, the agent was still effective in PG-deficient rats. The evidence that neostigmine markedly aggravated gastric damage caused by low doses of absolute ethanol and that atropine completely prevented this damage postulates mechanisms involving specific muscarinic receptor interactions.