High doses of cytosine arabinoside (ara-C) have been used in the treatment of refractory forms of acute nonlymphoblastic leukemia (ANLL) and ANLL occurring after previous antineoplastic therapy. In addition to the usual toxicities associated with antimetabolites, neurotoxicity, mainly in the form of cerebellar dysfunction, develops in a significant proportion of patients receiving high-dose cytosine arabinoside HDara-C. This study was performed to determine the incidence of cerebellar dysfunction in our patients and to determine any factors that predict its development. In this series of 30 consecutive patients receiving HDara-C, confusion with cerebellar signs and symptoms developed in seven (23%). Factors that appear to predispose patients to the development of neurotoxicity are (1) past history of neurologic dysfunction and (2) preexisting and progressive hepatic dysfunction. No peripheral neuropathy was seen. In contrast to previous reports, we did not find neurotoxicity to be dose related. Prophylactic use of pyridoxine does not prevent neurotoxicity.