Previous studies by us indicated that ethanol in concentrations of 2.0-4.8% produced subepithelial blebs in the jejunum of the hamster. In the rat, due to rupture of the blebs, there was denudation of the villus tip epithelium. There are nos similar data on humans. Ethanol, in quantities equivalent to 4.8-6.4 ounces of 80 proof whiskey (diluted to 20% w/v), was infused into stomachs of 20 normal human volunteers. Subjects were divided into groups (Gr) according to the amount or type of alcohol given, and site of biopsies (SB). Gr 1:60 g ethanol, SB = jejunum. Gr 2:45 g ethanol, SB = jejunum. Gr 3:45 g ethanol, SB = duodenum. Gr 4:45 g ethanol as 4.8 oz 80 proof whiskey, SB = duodenum. To compare the morphology in the absence and presence of ethanol, biopsies were obtained from each volunteer before ethanol administration (control period), immediately after peak ethanol concentration in the duodenum or jejunum (ethanol period), and when intraluminal ethanol concentration fell towards zero (recovery period). The mean peak intraluminal ethanol concentrations in the four groups varied between 5.69% and 9.37% (w/v). Ethanol-induced damage was evaluated using strict preset criteria. Coded slides were evaluated by two observers. Suction biopsy damaged 18% of the villi even in biopsies obtained during the control period. Ethanol produced a statistically significant increase in the number of damaged villi (mean of all groups 45%, range: 32% in Gr 2 to 62% in Gr 3). During the recovery period the number of damaged villi fell to that seen in control period biopsies. Ethanol, in quantities equivalent to those ingested during moderate drinking, may produce transient damage to the upper small intestine of man. Conversely, ethanol may simply increase the susceptibility of the mucosa to the unavoidable trauma of suction biopsy. However, the histological and ultrastructural changes were similar to those induced by ethanol in small laboratory animals.