Hepatocyte antigen is recognized by antibody Hep Par 1, a widely used diagnostic immunomarker for hepatocellular carcinoma and tumors with hepatoid differentiation. Hepatocyte antigen expression has also been detected in nonneoplastic small intestinal epithelium, but expression in small intestinal adenocarcinoma has not been well investigated. We immunohistochemically examined 39 nonampullary small intestinal adenocarcinomas for hepatocyte antigen expression; 34 cases contained normal-appearing nonneoplastic small intestinal mucosa on the same tissue sections. In 30 cases (88%), the nonneoplastic mucosa exhibited granular cytoplasmic Hep Par 1 staining exclusively in the epithelium. Only 9 small intestinal adenocarcinomas (23%) showed focal positive cytoplasmic staining. Nonneoplastic colonic epithelium was negative for Hep Par 1. In 31 colorectal adenocarcinomas, 3 (10%) showed positive staining for Hep Par 1 (1 diffuse, 2 focal), a frequency not different from that for small intestinal adenocarcinomas (P = .2467). Tumors expressing hepatocyte antigen did not exhibit evidence of hepatoid differentiation and were histologically indistinguishable from hepatocyte antigen-negative tumors. Hepatocyte antigen immunoreactivity is selectively expressed in nonneoplastic small intestinal enterocytes but not in colonocytes, suggesting a potential physiologic role in intestinal biology. Whether the loss of antigen expression in a large number of small intestinal adenocarcinomas serves a role in small intestinal tumorigenesis remains to be investigated.