Exposure of the small intestinal mucose to 6% ethanol (which is found in human jejunum during alcohol consumption) causes morphological alterations, and increased permeability of the mucosa and histamine release from intestinal mast cells. The released histamine is shown to mediate a significant component of the increased mucosal permeability (i.e., mucosal injury). In the present study, we have investigated whether adaptive cytoprotection occurs against the increased mucosal permeability and histamine release induced by 6% ethanol. Rabbits were used. In each animal, three adjacent segments of upper small intestine were pre-perfused for 30 min, and then perfused for 90 min in the following order control solution followed by control solution (control segment); control solution followed by 6% ethanol (ethanol segment); 1% ethanol followed by 6% ethanol (pretreated ethanol segment). During the 90-min perfusion, mucosal permeability of each segment was measured by analyzing the effluent for intraluminal clearance of i.v. administered 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA) and 125I-labelled bovine serum albumin (125I-BSA). Mast cell histamine release was assessed by determining histamine concentration of the gut effluent. All measurements were higher in the ethanol segments than in the controls. These ethanol effects were significantly lower in the pretreated ethanol segments, indicating that adaptive cytoprotection occurs against the mucosal injury induced by 6% ethanol. These findings are discussed in relation to the literature on mucosal effects of intestinal intraluminal ethanol.