This study determined the effects of chronic administration of the two principal proximate cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), on host wasting in rats. The effects were compared with those observed in a matched pair-fed group to distinguish the contribution from anorexia. Both TNF and IL-1 produced weight loss, net nitrogen loss, and skeletal muscle catabolism and increased liver weight. Such effects were independent from and additive to those resulting from semistarvation. However, under equivalent nutritional conditions, TNF infusion led to a greater effect on muscle protein catabolism and liver weight and caused liver protein anabolism, whereas only the group receiving IL-1 had altered glucose metabolism in the postabsorptive state. Tachyphylaxis was seen in the response of food intake over time after administration of IL-1. These actions define the two principal mechanisms for the development of protein calorie malnutrition that occur because of cytokine action, anorexia producing semistarvation and an increased net protein catabolic rate reducing anabolic efficiency.