Acute lymphoblastic leukemia (ALL) is the most common pediatric caner. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation and repair. The most common two polymorphisms are methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. We studied their effect on 30 ALL patients and 30 healthy controls regarding the incidence, toxicity and response to treatment using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). MTHFR 1298 AC showed a decrease in incidence of ALL (OR=0.5; 95% CI=0.28-0.8; P=0.01).Treatment toxicity with MTHFR C677T polymorphism was seen in the form of decreased platelet count (P=0.03) and with A1298C in the form of liver toxicity (P=0.03). No significant association could be found between the polymorphisms and response to treatment.