The transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a major regulator of genes encoding Phase II detoxifying enzymes and antioxidant proteins, is important for protecting cells against oxidative damage. In this work, we report that in the immune-mediated motor neuron injury animal model, expression of Nrf2 and antioxidative enzymes including glutathione S-transferase, nicotinamide adenine dinucleotide phosphate (reduced)-quinone oxidoreductase 1 and heme oxygenase 1 were greatly reduced in motor neurons of spinal cord anterior horn in paralyzed guinea pigs, whereas the antioxidant enzymes in the dorsal horn of paralyzed guinea pigs were generally preserved. Our findings suggest that declined antioxidative capacity may contribute to the damage to motor neurons in the process of immune-mediated motor neuron injury. Although the exact mechanism of immune reactivity and Nrf2-antioxidant response element pathway inactivation remains to be elucidated, inducers of Phase II detoxification enzymes may be an attractive therapeutic target for immune-mediated motor neuron degeneration.