Tumor necrosis factor (TNF) is widely accepted to be the mediator of the cascade of metabolic abnormalities associated with both critical and chronic illness. TNF binding to cell surface receptors mediates its physiologic actions, although the exact mechanism of TNF action is unknown. Therefore, this study was designed to investigate the in vivo metabolism of TNF using a mathematical model to examine tissue uptake and loss of TNF over time. Two distinct patterns of TNF uptake were observed. Muscle tissues were found to accumulate TNF over the entire experimental period, whereas the visceral organs were found to have a rapid initial accumulation of TNF followed by a rapid loss of TNF back to the plasma or out into the bile or the urine. These patterns of TNF binding and retention may reflect the number of TNF receptors or their affinity for TNF, as well as the balance between cell surface and soluble TNF receptors. Furthermore, TNF binding patterns provide insight into the biologic action of TNF at these sites.