Levamisole (LEV) has been used as an immunomodulating medication in patients with recurrent aphthous ulcers and as an adjuvant for chemotherapy. LEV, with or without 5-fluorouracil (5-FU), induces multifocal inflammatory leukoencephalopathy (MIL). We identified 31 patients with LEV-induced MIL: 7 from our institution and 24 from a MEDLINE search. Twenty-one patients (67.7%) had been treated with a combination of LEV and 5-FU, while 10 patients had been treated with LEV alone. The onset of MIL was delayed in patients who took LEV and 5-FU in combination compared with the patients treated with LEV alone (11.7 +/- 3.7 vs. 4 +/- 2.5 wk, p < 0.001). Colon cancer (67.7%) was the most common indication for LEV administration. Gait ataxia occurred in 20 (64.5%) patients, and dysphagia was noted in 16 (51.6%) patients. Imaging studies revealed periventricular enhancement in 17 (54.8%) patients and supratentorial lesions in 16 (51.6%) patients. Cerebrospinal fluid studies showed lymphocytic pleocytosis in 10 of 21 (47.6%) patients. Early diagnosis of MIL and discontinuation of LEV is essential, yielding good recovery in most cases. Treatment with corticosteroids and/or intravenous immunoglobulin may be needed for this serious inflammatory encephalopathy. Twenty-nine patients exhibited improved clinical status and imaging findings after initial steroid or immunoglobulin treatment. Plasmapheresis may be an alternative regimen for patients with steroid resistance.