To determine whether P450IIE1, a microsomal P450 enzyme inducible by ethanol in the liver, is also present and inducible in the alimentary tract, corresponding frozen tissue sections were prepared from rats pair-fed liquid diets containing 36% of total calories as either ethanol or carbohydrate (control) for 3 weeks. Immunohistochemical staining was performed using the peroxidase-antiperoxidase method after tissue sections were reacted with antibody against human P450IIE1. In control animals, immunoreactive P450IIE1 was detected only in duodenal and jejunal villous cells. After ethanol treatment, the content of P450IIE1 increased in duodenal and jejunal villi, and the enzyme was now also found in squamous epithelial cells of the cheek mucosa, tongue, esophagus, and forestomach, and in surface epithelium of the proximal colon. P450IIE1 was neither expressed nor induced by alcohol in the epithelium of stomach fundic and antral mucosa, ileum, distal colon, and rectum. When considered together with the xenobiotic activation properties of P450IIE1, these results may partly explain why alcohol abuse is a risk factor for cellular damage or cancer or both in those alimentary tract tissues in which P450IIE1 is inducible by chronic ethanol intake.