Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and gradual loss of motoneurons in the brain and spinal cord. A persistent inflammation, typified by the activation of astrocytes and microglia, accompanies the progressive degeneration of motoneurons. Interferon gamma (IFNc), a potent proinflammatory cytokine that is aberrantly present in the spinal cord of ALS mice and patients, has been proposed to contribute to motoneuron death by eliciting the activation of the lymphotoxin-b receptor (LT-bR) through its ligand LIGHT. However, the implication of IFNc in the pathogenic process remains elusive. Here, we show that an antagonistic anti-IFNc antibody efficiently rescues motoneurons from IFNc-induced death. When transiently delivered in the cerebrospinal fluid through a subcutaneously implanted osmotic minipump, the neutralizing anti-IFNc antibody significantly retarded motor function decline in a mouse model of ALS. However, this transient infusion of anti-IFNc antibody did not increase the life expectancy of ALS mice. Our results suggest that IFNc contributes to ALS pathogenesis and represents a potential therapeutic target for ALS.