The spontaneous release of LIF from blood lymphocytes was studied in patients with infectious mononucleosis. Mononuclear cells were separated from the blood and cultured for 22 hr, and LIF activity in the supernatant was determined. Supernatants depleted of LIF activity by means of anti-LIF antibodies or by treatment at 80 degrees C for 30 min were employed as controls; these two methods gave essentially similar results. In nine out of eighteen patients, spontaneous LIF production was demonstrated during the acute stage of the illness; this was not seen in any of the normal persons studied. 6 weeks later, spontaneous LIF production had ceased in most patients. Concanavalin A stimulated all normal lymphocytes to LIF production, but in sixteen out of seventeen patients with infectious mononucleosis this response was absent or diminished. At the follow-up study 6 weeks later, the lymphocyte response to concanavalin A was still suppressed.