Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling. Exposure of mice deficient in IRAK-M (IRAK-M(-/-)) to 95% oxygen resulted in reduced mortality compared with wild-type mice and occurred in association with decreased alveolar permeability and cell death. Using a bone marrow chimera model, we determined that IRAK-M's effects were mediated by structural cells rather than bone marrow-derived cells. We confirmed the expression of IRAK-M in alveolar epithelial cells (AECs) and showed that hyperoxia can induce the expression of this protein. In addition, IRAK-M(-/-) AECs exposed to hyperoxia experienced a decrease in cell death. IRAK-M may potentiate hyperoxic injury by suppression of key antioxidant pathways, because lungs and AECs isolated from IRAK-M(-/-) mice have increased expression/activity of heme oxygenase-1, a phase II antioxidant, and NF (erythroid-derived)-related factor-2, a transcription factor that initiates antioxidant generation. Treatment of IRAK-M(-/-) mice in vivo and IRAK-M(-/-) AECs in vitro with the heme oxygenase-1 inhibitor, tin protoporphyrin, substantially decreased survival and significantly reduced the number of live cells after hyperoxia exposure. Collectively, our data suggest that IRAK-M inhibits the induction of antioxidants essential for protecting the lungs against cell death, resulting in enhanced susceptibility to hyperoxic lung injury.