The present study was undertaken to investigate ultrastructurally the epithelium covering lymphoid nodules obtained from colonoscopic biopsies of the human colon and rectum. Colonoscopy using the dye spraying contrast method was performed in nine patients who showed x-ray evidence of lymphonodular hyperplasia. Fifty-two colonoscopical biopsy specimens of lymphoid nodules were obtained from the ascending, transverse, and descending colon and rectosigmoid region. All specimens were observed by light and electron microscopy. Light microscopy disclosed large lymphoid follicles protruding into the lumen with a "dome-type" configuration. These extended to the lamina propria of the mucosa and were associated with a massive lymphoid aggregation extending as far as the muscularis mucosa from the submucosa. The epithelium covering these nodules contained a few goblet cells and many lymphocytes. Observation of the elevated surface at the apex by scanning electron microscopy revealed M cells with sparse microvilli in the dome epithelium surrounded by crypts. Transmission electron microscopy disclosed M cells enfolding many immature or mature lymphocytes and plasmocytes. The M cells had cytoplasmic microvilli (so-called "microfolds") on their surfaces, well-developed tubulovesicular systems, and vacuoles in the cytoplasm. The basic structure of the M cells as observed by scanning and transmission electron microscopy was the same as that of M cells in the Peyer's patches of humans and mice. The apical surface of the colonic lymphoid follicles in Crohn's disease patients was associated with erosions observed by scanning electron microscopy. The erosions proved to be the naked surface of the dome after removal of the epithelium, and many holes from 2.0 to 6.0 microns in diameter were observed on the naked surface. At high magnification, lymphocytes were seen projecting from holes (18%) on the naked surface of the dome. These ultrastructural findings indicate that human colonic lymphoid follicles are very similar to those seen in other species.