To identify diffuse mucosal changes which may precede the development of colorectal cancer and a possible indicator for detecting high-risk populations, we immunohistochemically studied cell-cycle events in crypts of normal-appearing rectal mucosa of patients with colorectal adenoma and cancer using an in vitro labeling method with bromodeoxyuridine (BrdU). Biopsy specimens of endoscopically normal-appearing rectal mucosa were obtained during colonoscopy from 20 patients with colorectal adenocarcinoma, 20 with adenoma, and 15 without apparent colorectal diseases. The specimens were incubated with BrdU in vitro, and labeled S-phase cells were identified immunohistochemically using a monoclonal antibody to BrdU. Modification of the BrdU-labeling pattern in the normal appearing rectal mucosa, such as the presence of BrdU-labeled cells at the mucosal surface or in the upper one-fifth of the crypt column, was observed in 15 of the 20 patients with adenocarcinoma, 17 of the 20 patients with adenoma and 6 of the 15 controls. This upward shift in the frequency of proliferating cells in the crypt was significantly higher in the patients with colorectal adenoma and cancer than in the controls, and may be used to identify subjects at high risk for colorectal cancer.