The serum factor inducing hemorrhagic necrosis of transplantable tumors [tumor necrosis factor (TNF)], and the macrophage hormone associated with cachexia in cancer and certain infectious diseases [cachectin] are known to be the same protein. Because an association may exist between TNF and the cachectic state, we wished to examine the effect of TNF on the permeability of epithelial barriers. We present data showing that TNF affects the tight junctional region between epithelial cells, lowering the transepithelial resistance and potential difference, and increasing the flow of solute between cells and across the epithelium. These effects are dose dependent, rapidly reversible, and inhibited by a monoclonal antibody to TNF-α. We suggest that the release of TNF at various sites throughout the body will cause a general breakdown in the barrier function of an epithelial cell sheet. This may relate to the cachexia observed in certain disease states. These findings are similar to our earlier published effects of phorbol esters and diacylglycerols on tight junctions, suggesting that protein kinase C activation may be involved.