Encephalopathy is a serious adverse reaction occurring in 15-30% of patients treated with the alkylating agent ifosfamide. Patients with this adverse effect may experience seizures, drowsiness, confusion and hallucinations of different grades of severity. In this article, we describe five cases of acute CNS toxicity in patients aged > or =65 years of age treated with ifosfamide and we review data on the management and outcome of this serious complication in elderly patients. All five patients experienced symptoms of encephalopathy soon after receiving combination chemotherapy including ifosfamide for different tumours. All of the patients had been assessed by means of a Comprehensive Geriatric Assessment for the presence of associated diseases, disability, cognitive status and depression, and scores were satisfactory in all patients, although case 5 was deemed frail because of cancer-related limitation in movement. In four patients, the antidote methylene blue (methylthioninium chloride) was administered intravenously, with successful recovery in three patients and a fatal outcome in the fourth patient. The fifth patient rapidly recovered after discontinuation of ifosfamide and did not receive methylene blue. The roles of older age, peak ifosfamide concentration, low albumin levels, increased serum creatinine and bulky abdominal disease as predisposing factors for ifosfamide-related encephalopathy in retrospective series are controversial.Although methylene blue has been frequently administered in patients with ifosfamide-related encephalopathy, its efficacy in this context has not been assessed objectively. Thus, careful baseline evaluation of elderly patients and constant clinical observation during infusion, especially during the first course of therapy, are recommended to reduce the risk of severe CNS toxicity from ifosfamide.