Mononuclear cell (MNC) populations isolated from intestinal mucosa, mesenteric lymph nodes, and peripheral blood have been assessed for their natural killer (NK) (Leu-7+) cell proportions and NK cell activity against K-562 erythroleukemic target cells. In peripheral blood, normal proportions of Leu-7+ cells were found in patients with Crohn's disease or ulcerative colitis, whereas increased proportions in colorectal carcinoma may have been related to the higher mean age of these patients. Low proportions of Leu-7+ cells (< 3%) were present in intestinal MNCs in Crohn's disease, ulcerative colitis, colon cancer, and miscellaneous intestinal diseases. All groups of patients had diminished NK activity of peripheral blood MNCs compared with a group of healthy controls. Intestinal NK cell activity from histologically normal mucosa correlated with autologous peripheral blood NK cell activity (p < 0.001) but no such correlation was seen for patients with inflammatory bowel disease. Mucosal or nodal NK cell activity showed a wide range of activity but did not relate to the underlying disease, mucosal histopathology, drug therapy, or, in patients with cancer, Dukes' grading. Intestinal MNCs from all patient groups responded to stimulation with lymphoblastoid interferon, except in a small number of patients whose unstimulated activity was not detectable. In conclusion, the NK cell of intestinal mucosa behaves similarly in various intestinal diseases. However, the disparity between NK activity of autologous peripheral blood and intestinal MNCs in inflammatory bowel disease highlights the difficulty in extrapolating peripheral blood findings to mucosal immune events.