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Objective: To explore the effects of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism on the adverse reactions of high-dose methotrexate (MTX) in pediatric patients with acute lymphoblastic leukemia (ALL)., Methods: A total of 69 children with ALL admitted to the department of Pediatrics of Sun Yat-sen Memorial Hospital of Sun Yat-sen University from November 2018 to October 2020 were included in this study. The clinical data of the children were collected, leukocytes were isolated from their peripheral blood, and MTHFR genotyping was performed by digital fluorescence molecular hybridization techniques. The adverse reactions and plasma drug concentration of MTX were monitored during the chemotherapy. Moreover, the effect of MTHFR gene polymorphism on MTX adverse reactions and plasma drug concentration were analyzed., Results: Among the middle and high risk children, compared with the wildtype group (CC genotype), patients with MTHFR C677T mutations (CT+TT genotypes) had a higher risk of leukopenia ( OR =2.38), neutropenia ( OR =2.2), anemia ( OR =1.83) and hepatoxicity ( OR =1.98). However, no significant difference was found in the MTX plasma concentration between the MTHFR C677T mutantion group and the wildtype group at different timepoints (24 h, 48 h and 72 h). Multivariate analysis revealed that the plasma concentration of MTX (48 h), clinical risk level of ALL and MTHFR C677T gene polymorphism were independent factors for the adverse reactions of high-dose MTX., Conclusion: The MTHFR C677T mutations may be associated with myelosuppression and hepatotoxicity in children with ALL after high-dose MTX treatment.