Background. Idiopathic pneumonia syndrome (IPS) is a frequent and potentially fatal complication of bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-α (TNFα) in the bronchoalveolar lavage (BAL) fluid, and that administration of LPS to animals with extensive graft versus host exacerbated underlying lung injury (Blood 1996; 88: 3230). Methods. Lethally irradiated CBA mice received BMT from allogeneic (B10.BR) or syngeneic (CBA) donors. The role of TNFα in the exacerbation of pulmonary toxicity caused by LPS injection and in the evolution of IPS after allogeneic BMT was examined by neutralizing TNFα after BMT using a soluble binding protein (rhTNFR:Fc). Results. Five weeks after BMT, administration of rhTNFR:Fc dramatically reduced mortality and prevented the exacerbation of lung injury caused by LPS administration. This protective effect was associated with preservation of pulmonary function and with marked reductions of cells, neutrophils, and LPS in the BAL fluid of treated animals. TNFα neutralization from week 4 to 6 after allogeneic BMT effectively halted the progression of systemic GVHD and significantly reduced, but did not prevent lung injury that developed during the treatment period. Conclusions. We conclude that TNFα is central to early LPS induced toxicity in this model and is a significant, but not the exclusive contributor to the development of IPS after allogeneic BMT.