OBJECTIVES: This case report describes two cases of high-dose methotrexate-induced nephrotoxicity: death in the case of conventional supportive care and successful renal function recovery in a patient treated with glucarpidase and continuous dialysis. METHODS: High dose methotrexate is widely used for management of adult and pediatric malignancies. However, high-dose methotrexate-induced renal nephrotoxicity may cause severe, even lethal complications. Here we present examples of such outcomes. RESULTS: We present one case of lethal high-dose methotrexate nephrotoxicity in a patient treated with conventional rescue therapy. We contrast this outcome with another patient with high-dose methotrexate-induced anuric acute kidney injury, who has recovered renal function following therapy with glucarpidase and continuous dialysis. CONCLUSIONS: This is only the second reported case of high-dose methotrexate-induced anuric acute kidney injury, and the only one with a reported clinical outcome. This first report of recovery from high-dose methotrexate-induced anuric acute kidney injury after glucarpidase administration supports available evidence pointing to the effectiveness of this therapy.