Interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells (PBMC) in 14 patients with anorexia nervosa (AN) was significantly lower than in 14 age-matched healthy controls. Follow-up samples in four patients displayed low levels, except in two when they recovered the IFN-gamma production as the hormonal cycles were restored. A large interindividual variation for the lymphocyte proliferative response was observed in 30 AN patients. DNA synthesis of PBMC was normal in 8 patients (27%), significantly increased in 6 (20%) (P < 0.001), and significantly decreased in 16 (53%) (P < 0.001). IFN-gamma inhibition was reversed by culturing a control lymphocyte population with monocytes from patients with AN. This was not observed in cultures of control monocytes and AN lymphocytes. IL-2 receptor (TAC subunit) was assessed and no difference was found in the number of TAC-positive cells between patients and controls. These results point out impaired production of the immunomodulator cytokine IFN-gamma as a major functional defect of AN peripheral lymphocytes.