Intracerebroventricular microinfusion of recombinant human tumor necrosis factor (rhTNF) and recombinant human interleukin-1 beta (rhIL-1 beta) suppressed food intake in rats. Central infusion of heat-inactivated rhTNF and rhIL-1 beta, bovine serum albumin, heparin or transforming growth factor-beta had no such effect. Central infusion of rhIL-1 beta did not affect the dipsogenic response to central administration of angiotensin II. Peripheral administration of rhTNF and rhIL-1 beta in doses equivalent to or higher than those administered centrally had no effect. Electrophoretically applied rhTNF and rhIL-1 beta specifically suppressed the activity of glucose-sensitive neurons in the lateral hypothalamic area. Glucose-insensitive neurons were little affected. The results suggest that TNF and IL-1 beta act directly in the central nervous system to suppress feeding, and this effect may be operative during acute and chronic disease.