Purpose To assess a volume-weighted voxel-based multiparametric (MP) clustering method as an imaging biomarker to differentiate recurrent glioblastoma from delayed radiation necrosis. Materials and Methods The institutional review board approved this retrospective study and waived the informed consent requirement. Seventy-five patients with pathologic analysis-confirmed recurrent glioblastoma (n = 42) or radiation necrosis (n = 33) who presented with enlarged contrast material-enhanced lesions at magnetic resonance (MR) imaging after they completed concurrent chemotherapy and radiation therapy were enrolled. The diagnostic performance of the total MP cluster score was determined by using the area under the receiver operating characteristic curve (AUC) with cross-validation and compared with those of single parameter measurements (10% histogram cutoffs of apparent diffusion coefficient [ADC10] or 90% histogram cutoffs of normalized cerebral blood volume and initial time-signal intensity AUC). Results Receiver operating characteristic curve analysis showed that an AUC for differentiating recurrent glioblastoma from delayed radiation necrosis was highest in the total MP cluster score and lowest for ADC10 for both readers. The total MP cluster score had significantly better diagnostic accuracy than any single parameter (corrected P = .001-.039 for reader 1; corrected P = .005-.041 for reader 2). The total MP cluster score was the best predictor of recurrent glioblastoma (cross-validated AUCs, 0.942-0.946 for both readers), with a sensitivity of 95.2% for reader 1 and 97.6% for reader 2. Conclusion Quantitative analysis with volume-weighted voxel-based MP clustering appears to be superior to the use of single imaging parameters to differentiate recurrent glioblastoma from delayed radiation necrosis. © RSNA, 2017 Online supplemental material is available for this article.