In vitro immunoglobulin synthesis by isolated intestinal mononuclear cells of macroscopically normal mucosa from patients with Crohn's disease has been studied and results compared with those obtained with cells from normal mucosa of resection specimens from patients with colonic carcinoma, or other intestinal disorders. The total lamina propria mononuclear cells (LPMC) in Crohn's disease produced spontaneously less IgA and more IgG than the control groups, but no difference was observed for IgM. An enriched lymphocyte fraction (LPL) of the Crohn's disease patients showed a higher spontaneous synthesis of IgA and IgG when compared with controls. In contrast, another fraction enriched for macrophages (LPM) produced spontaneously less IgA, IgG, and IgM in Crohn's, than in control patients. Incubation with pokeweed mitogen (PWM) decreased immunoglobulin synthesis by LPMC in Crohn's disease and controls, and this was enhanced by simultaneous incubation with concanavalin A. In controls PWM stimulation increased immunoglobulin synthesis by LPL and decreased immunoglobulin synthesis by LPM. In Crohn's disease, however, PWM had no effect on either fraction. This study shows major differences in the regulation of the immunoglobulin synthesis by intestinal cells between Crohn's disease and controls.