Although local tumor necrosis factor-α (TNF) release by alveolar macrophages has been postulated to contribute to the development of acute respiratory distress syndrome (ARDS), the effects of instilling TNF intratracheally on the development of acute lung leak are not known. Our goal was to determine the effect of intratracheally administered TNF on the development of acute lung leak in rats. We found that rats given TNF (500 ng) 5 hours previously intratracheally had increased (p<0.05) lung lavage cytokine induced neutrophil chemoattractant (CINC) concentrations, lung lavage neutrophils, lung myeloperoxidase (MPO) activity, and lung leak compared to saline-treated control rats. However, all of the responses following TNF instillation were much lower than the responses to interleukin-1α (IL-1) instillation. For example, instilling 50 ng of IL-1 caused 6.4 times the increases in lung lavage CINC concentrations, 15.5 times the increase in lung lavage neutrophils, 3.6 times the increase in lung MPO activity and 3.8 times the increase in lung leak caused by giving 500 ng of TNF intratracheally. Cotreatment with TNF-binding protein decreased both lung MPO and lung leak increases in rats given TNF intratracheally. These observations suggest that locally elevated levels of TNF may induce lung neutrophil recruitment and acute lung leak but that IL-1 is a much more potent agent than TNF in causing lung neutrophil accumulation and lung leak.