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A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification. [Display omitted] • Single-cell analysis of on-treatment gliomas reveals cellular basis of drug responses • In responders, mutant IDH inhibitors induce lineage differentiation • The differentiation favors astrocytic-like over stem/progenitor-like states • NOTCH1 mutations modify the response and may serve to stratify patients The molecular response of IDH-mutant glioma to mutant IDH inhibitors is poorly understood. Spitzer et al. show that, in patients with clinical response, mutant IDH inhibitors induce lineage differentiation of cancer cells and deplete cells in a stem/progenitor-like state. They further highlight potential modifiers of such differentiation response in glioma. [ABSTRACT FROM AUTHOR]