A 75-year-old man developed subacute progressive muscle weakness and painful paresthesia of the left upper and right lower limbs. The patient had no history of diabetes mellitus. On physical examination, there was no evidence of icterus or hepatosplenomegaly. Palmar erythema without rash was noted. Neurologic examination revealed muscle atrophy and weakness in the left upper limb and mild muscle weakness in the right proximal lower limb. Dysesthesia, severe hypesthesia, and hypalgesia were found in the left upper limb. The tendon reflexes were decreased in the left upper limb and absent in the lower limbs. The cranial nerves were preserved on the day of admission, followed by the involvement of the right oculomotor nerve. Serological examination revealed a mixed IgG/IgM cryoglobulinemia and hepatitis C virus (HCV) infection with evidence of HCV virus replication by PCR for HCV RNA. The patient was diagnosed as having a mixed cryoglobulinemic neuropathy associated with HCV infection. Interferon-alpha therapy with 3 million units subcutaneously was initiated three times per week; however, there was no clinical improvement, although cryoglobulins became undetectable and the level of serum HCV RNA decreased remarkably. Intravenous immunoglobulin therapy 20 g per day for 5 days was also ineffective. The patient developed right facial nerve palsy, followed by right abducens nerve palsy. Treatment with prednisolone 40 mg per day improved and stabilized neurologic symptoms. Although interferon-alpha is considered to be a promising therapy for neurologic complications of HCV infection with mixed cryoglobulinemia, the optimal treatment remains unestablished.