Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-␣ (TNF-␣) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-␣ to the development of IPS has not been elucidated. Using a lethally irradiated parent 3 F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-␣, elevated numbers of donorderived TNF-␣-secreting T cells, and increased pulmonary macrophage production of TNF-␣ to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-␣ ؊/؊ donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-␣-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-␣ secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-␣ resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS.Collectively, these data demonstrate that donor TNF-␣ is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-␣ in the evolution of this process.