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This study was designed to evaluate the effect of Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on MTX toxicity in pediatric Egyptian ALL patients. Ninety- Four of Pediatric ALL patients aged 3-13 years (7.6 ± 3.6) on oral maintenance dose of 50 mg/m2 weekly of MTX. MTHFR c.677C>T (rs1801133) and c.1298A>C (rs1801131) genotyping were performed using polymerase chain reaction restriction fragment length polymorphism (PCR- RFLP). The allele frequencies of c.677C>T were 42.6%, 46.8%, and 10.6% for CC, CT, and TT respectively, while c.1298A>C alleles frequencies were 62.7%, 24.5%, and 12.8% for AA, AC, and CC respectively. None of the investigated polymorphism (C677T or A1298C alleles) was associated with either overall or site specific MTX toxicity regarding anemia (p = 0.99) (p = 0.4), platelets (p = 0.4) (p = 0.4), hepatotoxicity (p = 0.4) (p = 0.7), respectively. The results indicated that between c.677C>T genotypes, CC/CT and TT were associated with hematopoietic toxicities 60.7% and 60% (p = 0.2); platelet toxicities 76.2% and 80% (p = 1) and, hepatotoxicities 40.5% and 60% (p = 0.3), respectively. In the c.1298A>C genotypes, CC/AC and AA presented hematopoietic toxicities 68.6% and 55.9% (p = 0.2), platelet toxicities 82.9% 72.9% (p = 0.3) and, hepatotoxicity 37.1% and 45.8% (p = 0.5), respectively. No significant associations were detected between MTHFR c.677C>T or c.1298A>C polymorphisms and either overall or site specific MTX toxicity. [ABSTRACT FROM AUTHOR]