This study included 852 chemotherapy cycles with methotexate (Mtx), administered in the dose of 2 g/m2 and 3 g/m2 to 218 children with acute lymphoblastic leukemia. Prolonged Mtx elimination was observed in about 17% of cycles and 45% of patients. Major factors that affected Mtx elimination included: higer steady-state Mtx levels and impairment of drug clearance in the early phase of its rapid elimination. Considerable variability of Mtx pharmacokinetics, demonstrated in the study, is an argument for adapting the dose to a current, variable clearance of the drug in a given patient. In general tolerance of high doses of Mtx was good and was not associated with intensified (grade 3 and 4) or prolonged toxicities. The most common early complications were: hepatic dysfunction, nausea and vomiting and oral mucositis. The most significant factor affecting the intensity of early toxicity was prolonged exposure to cytotoxic concentrations of Mtx. The high risk group for intensified early toxicities of high doses Mtx therapy includes: patients with higher serum steady-state drug levels, characterized by slower drug elimination and lower coefficient of elimination in the early phase of drug excretion, children above 10 years of life and patients during the first chemotherapy cycle with Mtx.