Macrophage secretory products are suspected to participate in the severe lean tissue wasting related to chronic illness. The protein metabolic effects of chronic, 7-day cachectin/tumor necrosis factor (cachectin) or interleukin 1 alpha (IL-1 alpha) administration in vivo were studied in male Wistar rats that were 1) freely fed, 2) pair fed, 3) total protein and calorie starved, 4) twice daily lipopolysaccharide (LPS) administered, 5) twice daily cachectin administered, and 6) twice daily IL-1 alpha administered. LPS, cachectin, or IL-1 alpha administration produced anorexia; weight loss in these groups was comparable to respective pair-fed animals. However, LPS, cachectin, or IL-1 alpha accelerated peripheral protein wasting while preserving liver protein content, unlike the pattern in the pair-fed or starved animals in which loss of liver proteins and relative preservation of skeletal muscle protein were observed. The decrease in skeletal muscle protein content in LPS- or cytokine-treated animals was associated with coordinate decreases in muscle mRNA levels for the myofibrillar proteins myosin heavy chain, myosin light chain, actin, and in the 18S and 28S subunits of ribosomal RNA. We conclude that chronic exposure to the cytokines, IL-1 alpha or cachectin, can simulate those body and muscle protein changes seen in experimental LPS administration or chronic disease and markedly differ from the pattern of protein redistribution due to caloric restriction.