Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor–α (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR–KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR–KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was Increased and levels of an antioxidant enzyme reduced in brain cells of TNFR–KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury–induced microglial activation was suppressed in TNFR–KO mice, demonstrating a key role for TNF in injury–induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.