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Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo, and the Notch1 signaling pathway was suppressed by MBZ treatment.MBZ suppressed CCRF-CEM and CEM/C1 T-ALL cells at nanomolar concentrations.The chemoresistance of CEM/C1 did not affect MBZ-induced suppression.Notch1 signaling pathway was suppressed by MBZ treatments.MBZ inhibited chemoresistant CEM/C1 T-ALL cells in murine models.