Experimental autoimmune gray matter disease (EAGMD) is a model of both upper and lower motor neuron degeneration. EAGMD and amyotrophic lateral sclerosis (ALS) possess similar clinical and pathological features. The aim of this study was to find evidence of upper and lower neuronal damage in the EAGMD guinea pigs. The main ultrastructural alterations included abnormal mitochondria and disorganization of neurofilaments in the myelinated nerve fibers of the spinal cord. Swollen mitochondria and dilated endoplasmic reticulum were found in pyramidal cells of the motor cortex. The myelinated fibers in the cerebral peduncle showed atrophied axons and swollen mitochondria. Some motoneurons showed apoptosis-like signs. Pathological changes in the sciatic nerve manifest wallerian-like degeneration. Using immunofluorescence double labeling and confocal laser microscopy, IgG was colocalized with activated microglia in the ventral horn of the spinal cord. We also examined possible evidences of oxidative stress in the EAGMD guinea pig model and the role of p38 mitogen-activated protein kinase (p38MAPK) pathway in motor neuron degeneration. Our findings suggest that nitric oxide and peroxynitrite-mediated oxidative damage may play important roles in the pathogenesis of the neuronal degeneration in the spinal cord. Inflammatory cytokines such as TNF-alpha and IL-1 play important roles in the formation and acceleration of the spinal cord damage. The activation of p38MAPK signal pathway was involved in the development of the motor neuron degeneration of the spinal cord.