A model of ulcerative colitis related to cellular immunity has previously been produced by sensitization of the colon of guinea pigs with dinitrochlorobenzene (DNCB). We have confirmed and extended these studies in rabbits. Rabbits were skin-sensitized to DNCB and challenged 10 days later with an intrarectal instillation of DNCB. The histology of the colon was examined at various time intervals. Three days after challenge the mucosa was ulcerated; there were crypt abscesses and epithelial basophilia with increased mitotic figures. The increased inflammatory infiltrate in the lamina propria contained polyps as well as mononuclear cells. Submucous edema was common in this phase. This was compatible with active ulcerative colitis. These lesions changed to those consistent with the healing phase of ulcerative colitis at 2 weeks, and at 5 weeks there was still mild crypt disorganization and loss along with a paucity of goblet cells and submucous fibrosis. Rabbits that received repeated instillations of DNCB converted from a negative delayed hypersensitivity skin response to rabbit-colon extract to a positive response. Thus, a nonspecific cellular immune reaction in the colon produces histological changes compatible with ulcerative colitis and leads to the production of lymphocytes which are sensitized to colonic antigen.