Prostate apoptosis response‐4 (Par‐4), a protein containing a leucine zipper domain within a death domain, is up‐regulated in prostate cancer cells and hippocampal neurons induced to undergo apoptosis. Here, we report higher Par‐4 levels in lumbar spinal cord samples from patients with amyotrophic lateral sclerosis (ALS) than in lumbar spinal cord samples from neurologically normal patients. We also compared the levels of Par‐4 in lumbar spinal cord samples from wild‐type and transgenic mice expressing the human Cu/Zn‐superoxide dis‐mutase gene with a familial ALS mutation. Relative to control samples, higher Par‐4 levels were observed in lumbar spinal cord samples prepared from the transgenic mice at a time when they had hind‐limb paralysis. Immunohistochemical analyses of human and mouse lumbar spinal cord sections revealed that Par‐4 is localized to motor neurons in the ventral horn region. In culture studies, exposure of primary mouse spinal cord motor neurons or NSC‐19 motor neuron cells to oxidative insults resulted in a rapid and large increase in Par‐4 levels that preceded apoptosis. Pretreatment of the motor neuron cells with a Par‐4 antisense oligonucleotide prevented oxidative stress‐induced apoptosis and reversed oxi‐dative stress‐induced mitochondrial dysfunction that preceded apoptosis. Collectively, these data suggest a role for Par‐4 in models of motor neuron injury relevant to ALS.—Pedersen W. W., Luo H., Kruman, I., Kasarskis, E., Mattson, M. P. The prostate apopto‐sis response‐4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis. FASEB J. 14, 913–924 (2000)