The effects of chronic alcohol consumption on the ultrastructure of endothelial fenestrations in liver sinusoids were studied by scanning electron microscopy in surgical liver biopsies of 16 baboons pair-fed with nutritionally adequate diets containing alcohol or isocaloric carbohydrate for up to 112 months. Alcohol consumption for 4 to 24 months resulted in a decreased number of fenestrations (1.4 per μm2 of the endothelial surface vs. 3.3 in pair-fed controls; p < 0.01) and an increase in their geometric mean diameter (115.6 vs. 82.3 nm in controls; p < 0.001). After 61 to 112 months of alcohol feeding, the number of fenestrations was 1.9 (vs. 4.6 in controls; p < 0.005) and the fenestration diameter was 91.8 nm (vs. 76.7 nm in controls; p < 0.01). The fractional areas occupied by the fenestrations on the endothelial surface of the sinusoids in baboons fed alcohol for 4 to 24 and 61 to 112 months were calculated to be 84 and 58% of their respective controls. The alterations in the sinusoidal endothelium revealed in this study are most likely associated with a disturbance in the exchanges between the sinusoidal blood stream and the liver parenchyma and may thereby contribute to alcohol-induced liver injury.