Conflicting data have been reported on the effect of nicotine on gastric mucosal damage. To elucidate the effect of chronic intermittent nicotine on gastric mucosal damage, intragastric nicotine (5 mg/kg, 10 mg/kg) was administered twice per day for 9 days. Gastric mucosal damage was created by s.c. injection of a large dose (1.2 mg/kg) of pentagastrin followed by pylorus ligation for 6 hours. Nicotine treated rats showed reduced gastric mucosal damage about 50% of the control. To examine the mechanism of the protective effect of nicotine, gastric perfusion experiments were done. Basal acid secretion was not affected by intragastric or intravenous nicotine. However, pentagastrin-stimulated acid secretion markedly inhibited by a bolus injection of nicotine, and this response was dose-related. These data indicates that chronic intermittent administration of nicotine protects gastric mucosa against gastrin-induced gastric mucosal damage, and nicotine-induced inhibition of gastrin-stimulated acid secretion has an important role for the protective effect of nicotine. Considering reports concerning nicotine's aggravating effect on the gastric mucosal damage, it is suggested that the methods of administration of nicotine may be an important decisive factor of the divergent action of nicotine on the gastric mucosa.