Background Tumefactive demyelination (TD) is a relatively uncommon entity which mimics other focal intracranial lesions. Conventional radiological findings in tumefactive demyelination have been well described. However, DTI and MRS findings in TD have not been studied in detail. Purpose To evaluate the usefulness of conventional magnetic resonance imaging (MRI), multivoxel 1H spectroscopy (MRS) and diffusion tensor imaging (DTI) in diagnosis and follow-up of TD of the brain. Material and Methods Clinical and imaging findings of 18 patients were reviewed. MR imaging data which included conventional imaging as well as MRS and DTI were reviewed. At TE 135ms MRS various metabolite ratios were calculated at different depths of the demyelinating lesions. At TE 30 ms, glutamate-glutamine (GLX-2.1–2.5 ppm) was compared in the lesion to the contralateral normal side. DTI data were available for 15 patients and Dav (mean diffusivity) and trace values were recorded from central and peripheral layers of the index lesion. Histopathological (9 patients) and therapeutic response (9 patients) on follow-up imaging were taken as the diagnostic criterion. In addition, the follow-up MRI scans available were also reviewed. Results Characteristic peripheral ‘broken ring’ type of contrast enhancement was noted in 12 cases. Two or three concentric distinct zones were noted on imaging with distinct metabolic and structural signature in most cases. On TE 135ms, the central part showed variable Choline (Cho) and significantly low N-Acetyl Aspartate (NAA). DTI demonstrated high Dav and very low trace value in this zone. The intermediate area showed higher Cho and lower NAA compared to contralateral normal side. The outermost layer, which corresponded to the contrast enhancing areas on MRI, showed high Cho, lower NAA, and restricted diffusion on DTI. The GLX increase was noted in tumefactive lesions. Lactate was observed in all patients and it appeared higher at the center compared to the periphery of lesions. Follow-up imaging showed shrinkage of index lesions, disappearance of contrast enhancement, and diffusion restriction. MRS showed, persistent abnormalities on follow-up imaging. Conclusion Tumefactive demyelinating lesions reveal different microstructural changes at different depths of the lesion and this unique feature may be useful in differentiating them from other focal lesions of brain.