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Objective To investigate potential relationship between gene polymorphisms of ATP-binding cassette B1, C4 (ABCB1, ABCC4) and solute carrier organic anion transporter 1B1 gene(SLCO1B1) with methotrexate (MTX) blood drug concentration and high dose-MTX (HD-MTX)-related adverse events (AEs) in childhood acute lymphoblastic leukemia (ALL). Methods From January 2018 to December 2019, the blood samples were randomly collected from 275 hospitalized pediatric ALL patients in Beijing Children's Hospital of Capital Medical University. All patients were treated with HD-MTX. Chemiluminescent microparticle immunoassay (CMIA) was used to determine the MTX blood drug concentration at 45 h after infusion. Genotyping of ABCB1(rs1045642), ABCC4(rs7317112), and SLCO1B1(rs11045879 and rs10841753) were determined using MALDI-TOF MS based on MELPA technology. At the same time, chemotherapy-induced toxicity data including liver dysfunction, gastrointestinal disorder, mucositis, myelosuppression, and myocardial damage were recorded. The relationship of SNP polymorphism of these genes and MTX blood drug concentration with AEs were analyzed. Results All the genotypes analyzed were in Hardy-Weinberg equilibrium(P＞0.05). A statistically significant relationship between ABCC4 rs7317112 and SLCO1B1 rs11045879 genotype and 45 h MTX blood drug concentration was found(P＜0.05). The ABCC4 rs7317112 AA and AG genotypes and SLCO1B1 rs11045879 TT and TC genotypes may also be potential indicators for the excretion delay of MTX(P＜0.05). Conclusions ABCC4 rs7317112 and SLCO1B1 rs11045879 polymorphisms are potential genetic markers for individual MTX doses in the treatment of pediatric ALL patients.