We assessed the applicability of MP2RAGE for voxel-based morphometry. To this end, we analyzed its brain tissue segmentation characteristics in healthy subjects and the potential for detecting focal epileptogenic lesions (previously visible and nonvisible). Automated results and expert visual interpretations were compared with conventional VBM variants (i.e., T1 and T1 + FLAIR). Thirty-one healthy controls and 21 patients with focal epilepsy were recruited. 3D T1-, T2-FLAIR, and MP2RAGE images (consisting of INV1, INV2, and MP2 maps) were acquired on a 3T MRI. The effects of brain tissue segmentation and lesion detection rates were analyzed among single- and multispectral VBM variants. MP2-single-contrast gave better delineation of deep, subcortical nuclei but was prone to misclassification of dura/vessels as gray matter, even more than conventional-T1. The addition of multispectral combinations (INV1, INV2, or FLAIR) could markedly reduce such misclassifications. MP2 + INV1 yielded generally clearer gray matter segmentation allowing better differentiation of white matter and neighboring gyri. Different models detected known lesions with a sensitivity between 60 and 100%. In non lesional cases, MP2 + INV1 was found to be best with a concordant rate of 37.5%, specificity of 51.6% and concordant to discordant ratio of 0.60. In summary, we show that multispectral MP2RAGE VBM (e.g., MP2 + INV1, MP2 + INV2) can improve brain tissue segmentation and lesion detection in epilepsy. © 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.