A retrospective analysis of 14 patients who presented with a progressively expanding mass lesion(s) shown at biopsy/autopsy to represent acute demyelination was carried out. The aims of this study were to determine the optimal neuropathological approach to diagnosis and to determine the clinical evolution of this condition. Subsequent investigations and clinical outcome studies confirmed MS in 10 cases. Two patients had received an incorrect neuropathologic diagnosis of astrocytoma resulting in cranial irradiation. Key histologic parameters in establishing a diagnosis of acute demyelination were a predominance of lipid filled macrophages, macrophage alignment along axons, and an absence of oligodendroglial inclusions. Axonal injury was present in all cases and a lymphocytic/plasma cell infiltrate was sparse in areas of demyelination. Neuroimaging revealed single lesions in 10 patients and multiple lesions in 4 patients. Two patients were lost to follow-up, 3 died within 18 months of diagnosis, 8 had a relapsing remitting clinical course, and 1 patient had a chronic progressive course. In conclusion, a dense lymphocytic and plasma cell infiltrate is unusual in acute human demyelination. Although axonal injury is a frequent histologic finding in acute demyelination, it does not preclude a favorable clinical outcome.