Tumefactive demyelinating lesions (TDLs) can mimic a neoplasm on conventional imaging and may necessitate biopsy for diagnosis. The purpose of this study was to differentiate TDLs from high grade gliomas based on physiologic (permeability) and hemodynamic (blood volume) parameters using perfusion CT. Five patients who presented with tumefactive enhancing lesions on initial MRI that mimicked a neoplasm underwent perfusion CT. We compared the perfusion CT parameters of these patients with those of 24 patients with high grade gliomas. TDLs showed lower permeability surface area product (PS) (0.8 +/- 0.2 vs 2.4 +/- 1.4 ml/100 g/min, P-value 0.014) and lower cerebral blood volume (CBV) (1.0 +/- 0.2 vs 2.8 +/- 1.2 ml/100 g, P-value 0.006) as compared to high grade gliomas. TDLs show lower PS and CBV as compared to high grade gliomas, to which they can mimic on conventional MR imaging, due to lack of neoangiogenesis and vascular endothelial proliferation and hence perfusion CT can be used to differentiate the two entities.