Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Tumefactive MS (TMS) is a subtype of MS characterized by solitary or multiple mass lesions with open-ring enhancement on brain magnetic resonance imaging (MRI). Three TMS cases, diagnosed histopathologically by brain biopsy, that were difficult to distinguish from brain tumors or brain abscesses on MRI are presented. On T2-weighted imaging (T2WI) the lesions were high intensity in the center and periphery, with open-ring contrast enhancement at the periphery; iso- to low intensity areas ("T2 low rim") were seen in the surrounding region. Histopathological examination revealed the characteristic features of TMS: severe central demyelination and focal necrosis, peripheral neovascularization and perivascular inflammatory cell infiltration, and perifocal edema. On immunochemistry, both the endothelial cells of the neovasculature and the surrounding macrophages in the periphery expressed vascular endothelial growth factor and monocyte chemoattractant protein-1, which mediate inflammation and angioneogenesis and increase vascular permeability. These findings correspond to the T2 low rim co-localizing with the site of gadolinium enhancement on MRI. Thus, the present study clearly demonstrates the correlation between the radiological features and the pathophysiological aspects of TMS, which may contribute to more precise diagnosis of TMS.