Tumor necrosis factor-α (TNF-α) is a principal cytokine that may induce weight loss in malignancies and certain chronic infections. Short-term caloric deprivation has been found to facilitate in vitro TNF-α production, while increased spontaneous production of TNF-α has been found in patients with anorexia nervosa (AN). In the present work, we studied in vitro TNF-α production in other types of chronic undernutrition and the changes in TNF-α production during the refeeding of patients with AN. Undernutrition was evaluated by calculating fat body mass (FBM) from skinfold measurements and lean body mass (LBM) by total body potassium (TBK) counting. Spontaneous and induced TNF-α production by peripheral blood mononuclear cells (PBMC) was studied in six chronically malnourished patients with no intercurrent infections, seven patients with AN, and 16 age-matched normal healthy subjects. Spontaneous TNF-α production was in the normal range in the chronically undernourished subjects (4.3 ± 1.5 v 5.0 ± 1.9 U/mL), but significantly increased in the seven patients with AN (221 ± 327 v 5.0 ± 1.9 U/mL, P < .0006). During refeeding of patients with AN, TNF-α production decreased to the normal range concomitantly with weight gain. We concluded that chronic undernutrition, in general, is not always associated with increased TNF-α production and that it still remains to be determined whether TNF-α plays a primary role in the pathogenesis of AN.