Nicotine, while an important component of cigarettes, does not cause gross gastric mucosal damage, although its microscopic effect remains unknown. We have evaluated the histology and the microvascular permeability of (a) the effect of nicotine alone or in combination with ethanol on the gastric mucosa of rats and (b) the effect of feeding and sucralfate on the mucosa of rats treated with nicotine and ethanol. Mucosal injury was assessed histologically by the depth of injury and microvascular permeability by the leakage of fluorescein isothiocyanate-labelled albumin. Our results show that nicotine induced microscopic mucosal damage and accentuated the damage induced by alcohol. The damaging effects on mucosa of nicotine and ethanol, alone or in combination, were reduced by pretreatment with sucralfate. Similarly, feeding reduced the degree of mucosal injury. Nicotine and ethanol increased leakage of albumin into the interstitium and the leakage was reduced after sucralfate pretreatment. This study substantiates the adverse effect of smoking on mucosal damage. Vascular factors are probably involved in the pathogenesis.