Multifocal leukoencephalopathy and sensory-motor polyneuropathy have not been reported as side-effects of long-lasting interferon alpha therapy in a single patient. In a 77-year-old man interferon alpha2b and interferon alpha2a were administered subsequently but continuously since 1984 for hairy cell leukemia. Since early 2000, left-sided hemi-hypesthesia occurred and the patient developed gait disturbance, proximal weakness of the lower limbs, bilateral stocking-type sensory disturbances, and restless leg syndrome. Repeated cerebral magnetic resonance images showed multifocal T2-hyperintense white matter lesions supratentorially. The nerve conduction velocity of the peroneal and sural nerve was reduced. After exclusion of various differential diagnoses of leukoencephalopathy and application of a screening program for polyneuropathy, central and peripheral nervous system abnormalities were attributed to the long-lasting interferon alpha therapy. In single patients abnormally long-lasting interferon alpha therapy may cause multifocal white matter lesions supratentorially and sensory-motor polyneuropathy.