Clofarabine is used as second-line therapy for acute myeloid leukemia. Acute renal impairment is reported with clofarabine; however, it is more likely to occur in patients with confounding factors that may underlie the adverse event. We describe a 65-year-old man treated with clofarabine for relapsed acute myeloid leukemia who experienced severe acute kidney injury and proteinuria temporally related to clofarabine administration. The morning after completion of clofarabine administration, his serum creatinine concentration increased to approximately 1.4-fold above his baseline value, and peaked at 2.8-3.6-fold over baseline within 72 hours. A 24-hour urine collection contained 4100 mg of protein. His serum creatinine concentration gradually returned to within 1.5 times his baseline value. Examination of the patient's clinical course, vital signs, and laboratory results did not yield any compelling evidence of alternative causes for acute kidney injury. The patient's comorbidities included a left ventricular ejection fraction of 35-40% and diabetes mellitus. His drug therapy with potential renal effects-lisinopril, furosemide, tobramycin, allopurinol, and valacyclovir-that preceded clofarabine administration was evaluated, and none was determined to be a major factor in the development of this adverse event. Bone marrow evaluations were negative for residual leukemia after clofarabine therapy. After approximately 11 weeks of hospitalization, the patient and his family made an informed decision to continue supportive care at home. Acute kidney injury in this patient was attributed to clofarabine administration due to the time course of events with respect to potential contributing factors. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of renal effects and clofarabine therapy. To our knowledge, this is the first report of medically significant proteinuria associated with administration of clofarabine. Clinicians should be aware of the potential for acute kidney injury if their patients are administered clofarabine.