Purpose: Methotrexate (MTX) is one of the most widely used anticancer agents, with indications and established protocols in a range of childhood and adult cancers. High dose MTX (HD-MTX) requires aggressive care to prevent toxicity. Limited inpatient conditions are forcing major changes in health care delivery patterns and decisions. We conducted a retrospective study to describe the safety, feasibility and cost-effectiveness of HD-MTX administration in the outpatient setting. Methods: Patients with acute lymphoblastic leukemia who underwent HD-MTX ($3g/m^2$) administration in either the inpatient (N=70) or outpatient setting (N=70) from January to July 2012 were included. In the outpatient setting, HD-MTX was administered intravenously (IV) over 6 hours and included hydration with sodium bicarbonate ($2000ml/m^2$/ for 12 hours). Daily visits to the outpatient setting followed. Leucovorin was given 24 hours after MTX at a standard dose ($15mg/m^2$ IV bolus) every 6 hours. We compared the serum drug levels of MTX, hematologic and renal toxicity, hepatotoxicity, frequency of subsequent unscheduled outpatient visits and readmission episodes, medical expenses and duration of hospital stay between the two groups. Results: HD-MTX administrations were successfully completed in both groups. No significant differences were found between the two groups for the parameters studied. Patients who received HD-MTX in the inpatient setting had 2.37 times and 2.24 times greater medical expenses and duration of hospital stay respectively than outpatient recipients. Conclusion: This study suggests that HD-MTX administration done with aggressive monitoring in the outpatient setting is safe and efficient, without a greater incidence of major toxicities.