Surgical biopsy specimens of multiple sclerosis plaques have been only infrequently reported, and the scanty descriptions of these specimens have generally emphasized the inflammatory nature of the lesion. We present surgical specimens from four patients with multiple sclerosis on whom biopsies were performed because of clinical features mimicking brain tumor. Both general pathologists and neuropathologists involved with these cases experienced difficulty in arriving at the correct diagnosis. In all four cases, the lesions were remarkably uniform in microscopic appearance, consisting of monotonous sheets of gemistocytic astroglia interspersed by numerous foamy macrophages. In sections stained with hematoxylin-eosin, the most helpful diagnostic features were the even distribution of the foamy macrophages and the absence of associated necrosis. In each case, the diagnosis was confirmed with special stains that disclosed total destruction of myelin sheaths with relative preservation of axons. Significant inflammatory infiltration was present in only one of five biopsy specimens.