Non-major histocompatibility complex-restricted cytotoxicity or natural killer (NK) activity could be detected in all intestinal lamina propria mononuclear cell preparations of histologically normal mucosa from 57 patients with gastrointestinal disease. Similar levels of NK activity were detected among the different disease groups. Within the inflammatory bowel disease patient group, however, Crohn's disease patients showed a threefold higher level of NK activity than detected in ulcerative colitis patients. Cytotoxicity levels in Crohn's disease patients were also higher than in the control carcinoma patients, whereas ulcerative colitis patients had considerably lower cytotoxicity levels than the carcinoma patients. Thus, unaffected normal inflammatory bowel disease mucosa conceals alterations in NK activity which might occur before the inflammation. The colon adenocarcinoma cell line Caco-2 was found to be a representative target for detecting individual differences in NK activity of lamina propria mononuclear cells compared with standard K-562 targets. The latter can be of relevance when studying mucosal immunoregulatory mechanisms in intestinal disease.