There have been no prior reports of central nervous system toxicity following arsenic trioxide in patients with solid tumors. We report three metastatic urothelial carcinoma patients who were treated with arsenic trioxide (0.24 mg/kg/d 3-hour intravenously on days 1-6 weekly for 4 of every 5 weeks) who developed a clinical symptom complex characterized by confusion, word-finding difficulty, and behavioral changes. These symptoms appeared between day 26 and day 45 and resolved spontaneously in 1 patient. Two patients' symptoms did not resolve and they died of progressive urothelial carcinoma on days 47 and 90, respectively. Neuroimaging, lumbar puncture, and laboratory investigations did not reveal other causes. Arsenic trioxide in this dose and schedule can cause acute encephalopathy in patients with metastatic urothelial carcinoma who have received previous chemotherapy.