Despite numerous reports of morphologic characteristics of premalignant and malignant large intestinal epithelium, the literature lacks comprehensive reports of the morphologic features of the epithelium of the normal large intestine, except of the rectum. Large intestinal epithelium from 41 persons was obtained, and samples from the ascending, transverse, descending, and rectosigmoid areas were studied by light microscopy, histochemical techniques, and transmission and scanning electron microscopy. The morphologic features and histochemical reactions of the various segments of the large intestine are different. Neutral mucopolysaccharide is predominant in the ascending colon, whereas the rectum has predominantly or exclusively acidic mucin. Only three basic epithelial cell phenotypes have been identified: undifferentiated cells, mucous cells, and endocrine cells. The columnar cells at the surface between the crypts appear to be a variant of mucous cells. Compared with other segments, the rectum shows an unusually high concentration of endocrine cells, positively correlating with the high incidence of carcinoid tumors in that segment of the large intestine. The mucous cells in all segments contain large mucous vacuoles and small apical vesicles. The apical vesicles show variable electron density, being most dense in the ascending colon and becoming progressively less dense at the transverse and descending colon and most electron-lucent in the sigmoid colon and rectum. Ultrastructurally, the mucin shows a variable degree of heterogeneity in the proximal segments. This study suggests that some of the previously described ultrastructural features of abnormal large-intestinal epithelium may be only the result of failure to compare the so-called abnormal cells with normal cells from the same region. Well-controlled studies of the abnormal epithelium of a particular segment of large intestine must include the normal epithelium from the identical segment as control in order to make interpretations accurate.