ObjectivesTo evaluate the multiparametric diagnostic performance with non-enhancing tumor volume, apparent diffusion coefficient (ADC), and arterial spin labeling (ASL) to differentiate between atypical primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM).MethodsOne hundred and fifty-eight patients with pathologically confirmed typical PCNSL (n= 59), atypical PCNSL (hemorrhage, necrosis, or heterogeneous contrast enhancement,n= 29), and GBM (n= 70) were selected. Relative minimum ADC (rADCmin), mean (rADCmean), maximum (rADCmax), and rADCmax-min(rADCdif) were obtained by standardization of the contralateral white matter. Maximum cerebral blood flow (CBFmax) was obtained according to the ASL-CBF map. The regions of interests (ROIs) were manually delineated on the inner side of the tumor to further generate a 3D-ROI and obtain the non-enhancing tumor (nET) volume. The area under the curve (AUC) was used to evaluate the diagnostic performance.ResultsAtypical PCNSLs showed significantly lower rADCmax, rADCmean, and rADCdifthan that of GBMs. GBMs showed significantly higher CBFmaxand nET volume ratios than that of atypical PCNSLs. Combined three-variable models with rADCmean, CBFmax, and nET volume ratio were superior to one- and two-variable models. The AUC of the three-variable model was 0.96, and the sensitivity and specificity were 90% and 96.55%, respectively.ConclusionThe combined evaluation of rADCmean, CBFmax, and nET volume allowed for reliable differentiation between atypical PCNSL and GBM.Key Points•Atypical PCNSL is easily misdiagnosed as glioblastoma, which leads to unnecessary surgical resection.•The nET volume, ADC, and ASL-derived parameter (CBF) were lower for atypical PCNSL than that for glioblastoma.•The combination of multiple parameters performed well (AUC = 0.96) in the discrimination between atypical PCNSL and glioblastoma.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00330-023-09681-2.