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Objective: The T2-FLAIR mismatch sign is a useful imaging sign in clinical magnetic resonance imaging studies for detecting isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted astrocytomas. However, the association between the mismatch sign and pathologic findings is poorly understood. Therefore, the aim of this study was to elucidate the relationship of histopathologic and radiologic features with the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. Methods: We divided 17 IDH-mutant 1p/19q non-codeleted patients into 2 groups according to mismatch sign presence (WITH, n = 9; WITHOUT, n = 8) and retrospectively analyzed their pathologic findings and apparent diffusion coefficient (ADC) values. We also compared these findings between the tumor Core (central area) and Rim (marginal area). Results: In the pathologic analysis, Core of the WITH group contained numerous microcysts whereas Rim had abundant neuroglial fibrils and cellularity. In contrast, Core of the WITHOUT group had highly concentrated neuroglial fibrils. In ADC analysis, Core of the WITH group had significantly higher ADC values compared with Rim (P < 0.001). However, there was no significant difference between Core and Rim in the WITHOUT group (P = 0.12). The WITH group had a significantly higher Core/Rim ratio of ADC values compared with the WITHOUT group (P < 0.001). Conclusions: This study provides evidence that a region-dependent microstructural difference could reflect the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. Core of the mismatch sign characteristically had microcystic changes accompanied by higher ADC values, whereas Rim had abundant neuroglial fibrils and cellularity accompanied by lower ADC values.