Peripheral neuropathy is common in patients with hepatitis C virus infection and cryoglobulinemia. Here, we report a patient with axonal polyneuropathy associated with type III mixed cryoglobulinemia and hepatitis C virus infection without significant liver disease, who was successfully treated with pegylated interferon-alpha-2a and ribavirin. This case illustrated that clinical improvement was paralleled by a decrease of cryocrit but not necessarily by a decrease of viral replication rate. Treatment of hepatitis C virus-cryoglobulinemia-associated neuropathy should therefore be continued even if response of viral replication is lacking or delayed as long as a clinical benefit can be observed.