PURPOSE To investigate the diagnostic value of F-fluoroethyl-L-tyrosine (FET) positron emission tomography (PET) in patients with suspected tumefactive demyelinating disease. METHODS We retrospectively examined FET-PET and MR imaging of 21 patients (12 female, 9 male) with known demyelinating disease and newly diagnosed tumefactive lesions. The maximum standardized uptake value (SUVmax), time activity curves (TAC) and lesion-to-background ratio (TBR) of these lesions were calculated. The standard of reference consisted of biopsy and/or follow-up imaging. FET parameters of true neoplastic lesions and tumefactive demyelinating lesions were compared using Mann-Whitney U-test and receiver operating characteristic (ROC) analysis. RESULTS Nine patients (42.9%) had neoplastic lesions, 12 patients (57.1%) had tumefactive demyelinating lesions. TBRmax, SUVmax and TAC were significantly different between demyelinating lesions and neoplastic lesions: Tumors had a higher TBRmax (3.53 ± 1.09 vs. 1.48 ± 0.31, respectively; P < 0.001) and SUVmax (3.95 ± 1.59 vs. 1.86 ± 0.50, respectively; P < 0.001) than tumefactive demyelinating lesions. The TAC of tumors was significantly higher compared to tumefactive demyelinating lesions at all time points (P < 0.05). ROC analysis revealed that a TBRmax threshold of 2.2 and a SUVmax threshold of 2.5 could reliably differentiate tumor and tumefactive demyelination (area under the curve, 1.000 and 0.958, respectively). CONCLUSION In patients with demyelinating disease, FET-PET parameters TBRmax (cut-off 2.2) and SUVmax (cut-off 2.5) are able to distinguish tumefactive demyelinations from true neoplastic lesions.