We studied the in vitro effect of indomethacin, hydrocortisone, sulphasalazine, and its metabolites sulphapyridine (SP) and 5-amino salicylic acid (5-ASA) on peripheral blood mononuclear cells (PBMC) from 49 patients with inflammatory bowel disease and 34 controls. Indomethacin caused a highly significant increase in the PBMC response to the mitogen PHA-P compared with controls (P less than 0.01), indicating increased activity of a prostaglandin-producing suppressor cell system. On the contrary, sulphasalazine resulted in a reduced response which was significantly greater for the group with inflammatory bowel disease than the control group (P less than 0.05). This reduction was also produced by 5-ASA (P less than 0.05) but not by sulphapyridine. Addition of indomethacin to PBMC incubated with sulphasalazine significantly reduced the effect of sulphasalazine (P less than 0.001). Hydrocortisone resulted in a reduced response which was similar to that of controls and was not altered by the addition of indomethacin. The response to indomethacin, hydrocortisone, sulphasalazine, sulphapyridine, and 5-ASA was not dependent on the HLA type of the patients, disease activity, or drug therapy. The results suggest that increased suppression by a population of prostaglandin-producing suppressor cells plays a role in the immunopathology of inflammatory bowel disease, but that sulphasalazine does not exert its therapeutic effect by acting on this step of the immunoregulatory system. Any trials of indomethacin therapy in inflammatory bowel disease should take into account that, in vitro, sulphasalazine and indomethacin have opposing mechanisms of action in this system.