Freeze fracture replicas of the plasma membrane and tight junctions of epithelial cells of the terminal ileum from 10 patients with Crohn's disease involving the small bowel and from the terminal ileum of two patients without inflammatory bowel disease were studied to determine if significant morphological variations could be documented. Samples of diseased tissue were taken from: 1) macroscopically normal ileal resection margins, 2) pinpoint aphthoid ulcers, 3) small 5 mm ulcers, 4) cobblestone mucosa. Samples of ileal mucosa from the proximal margin of ileocolic resections for carcinoma of the right colon were identically processed and served as controls. Control specimens showed normal villus structures lined by absorptive and goblet cells linked to adjacent cells by four to seven tight junction strands, arranged as an anastomosing network of fibrils oriented perpendicularly to the long axis of the cell. Crohn's disease specimens taken from the cobblestone area displayed the greatest degree of tight junction disorganization. Tight junctions commonly formed bizarre patterns, were fragmented, and often showed misalignment in a direction parallel to the cell axis. Specimens taken from areas 2 and 3 displayed a less severe form of tight junction rearrangement. Junctional strand fragmentations, as well as areas of plasma membrane lacking strands, were apparent. The resection margins had minor irregularities in junctional structure in some, but not all, cases. The predominant alteration in those cases which showed change was varying degrees of strand fragmentation. We postulate that the tight junction abnormalities of epithelial cells from the terminal ileum of patients with Crohn's disease may contribute to a disturbance in barrier functions.