This study compares axonal injury in active, inactive, and remyelinated lesions in multiple sclerosis (MS) and chronic autoimmune encephalomyelitis (EAE). Axonal injury was quantified using immunoreactivity for beta-amyloid precursor protein (βAPP) in 22 MS patients and 18 rats with MOG-induced EAE. The highest incidence of acute axonal injury was found in active demyelinating lesions, with damage also present in inactive demyelinated plaques. Remyelinated shadow plaques showed no significant axonal damage. Axonal pathology in chronic active EAE was similar to that in MS, indicating that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies. Axonal damage was also observed in periplaque and normal white matter in active lesions, and in inactive lesions with active borders. Inactive lesions showed lower axonal damage compared to active ones. Remyelination protected axons from further damage. The study confirms that axonal destruction occurs during active demyelination in MS and that ongoing axonal damage in inactive lesions may contribute to clinical progression. The results emphasize the importance of axonal injury in MS and suggest that MOG-induced EAE is a useful model for studying axon-protective strategies in inflammatory demyelinating diseases.This study compares axonal injury in active, inactive, and remyelinated lesions in multiple sclerosis (MS) and chronic autoimmune encephalomyelitis (EAE). Axonal injury was quantified using immunoreactivity for beta-amyloid precursor protein (βAPP) in 22 MS patients and 18 rats with MOG-induced EAE. The highest incidence of acute axonal injury was found in active demyelinating lesions, with damage also present in inactive demyelinated plaques. Remyelinated shadow plaques showed no significant axonal damage. Axonal pathology in chronic active EAE was similar to that in MS, indicating that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies. Axonal damage was also observed in periplaque and normal white matter in active lesions, and in inactive lesions with active borders. Inactive lesions showed lower axonal damage compared to active ones. Remyelination protected axons from further damage. The study confirms that axonal destruction occurs during active demyelination in MS and that ongoing axonal damage in inactive lesions may contribute to clinical progression. The results emphasize the importance of axonal injury in MS and suggest that MOG-induced EAE is a useful model for studying axon-protective strategies in inflammatory demyelinating diseases.