This study was designed to investigate the mechanisms through which tumor necrosis factor ( Tnf) modulates ozone (O3)-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type ( wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [ TNFR1(−/−)], the p75 TNF receptor [ TNFR2(−/−)], or both receptors [ TNFR1/TNFR2(−/−)] were exposed to 0.3 parts/million O3for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(−/−) mice had significantly less O3-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O3elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(−/−) and TNFR1(−/−) mice, respectively. Airway hyperreactivity induced by acute O3exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wtmice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O3-induced pulmonary epithelial injury and inflammation and in acute O3-induced airway hyperreactivity.