Lewis-related blood group antigens are carbohydrate determinants carried on surface glycoproteins and glycolipids of erythrocytes and some epithelial cells. Their expressions in colorectal mucosa has been considered either as a marker of differentiation antigens or of tumor associated antigens. We prospectively studied Lewis-related blood group antigens in patients undergoing colectomy for colonic adenocarcinoma. Immunohematological studies were performed on preoperative blood samples and ABO and Lewis blood groups were determined. Tissue samples were obtained from the adenocarcinoma and from the adjacent non-neoplastic mucosa. The degree of tumor differentiation (grade of the tumor) was analyzed on hematoxylin and eosin stained slides. Immunoperoxidase staining was performed using antibodies against A, B, Le(a), Le(b), Le(x), and Le(y) antigens. The staining results of the colonic carcinoma were compared with those of the non-neoplastic mucosa and with the patient's red blood cell Lewis phenotype. A total of 22 patients were studied, 12 males and 10 females, with an average age of 64 +/- 12 years. There were 12 modified Dukes B and 10 modified Dukes C carcinomas. Le(a), a marker of differentiation antigens, was expressed in the non-neoplastic mucosa of 82% of the specimens. Le(y), a marker of tumor associated antigens, was detected in 77% of the carcinomas while expressed only in 18% of the adjacent non-neoplastic mucosa. Le(x), supposedly a marker for tumor aggressiveness, was found in 55% of the carcinomas. However, it was virtually absent in the five carcinomas which did not invade the pericolic tissues.