First-line therapy for hepatitis C virus (HCV) infection comprises interferon-alpha (IFN-alpha) and ribavirin for 6 or 12 months. Mild complications of therapy are common, but more serious complications are rare. Three patients with chronic HCV infection, acquired through injecting drug use, developed idiopathic facial paralysis (Bell's palsy) during therapy, with spontaneous resolution after withdrawal of treatment. Large-scale cohort studies reveal that IFNs are associated rarely with neurologic complications, and only one previous report has linked IFN-alpha therapy and Bell's palsy. We postulate that IFN-alpha therapy led to a breakdown of peripheral tolerance to myelin sheath antigens, leading to neuropathy, just as IFN-alpha therapy can cause autoimmune thyroiditis through breakdown of tolerance to native thyroid antigens.