Mixed cryoglobulinemia is one of the most closely related extrahepatic manifestations of hepatitis C virus and requires a challenging therapeutic approach depending on the severity of the symptoms. Here, we describe the long-term follow-up of a patient with important cutaneous, articular and neural manifestations of cryoglobulinemia associated with chronic hepatitis C treated with rituximab. A 42-year-old woman who did not respond to previous interferon-based treatments (standard and pegylated interferon plus ribavirin) and corticosteroids was subjected to treatment with rituximab at a dose of 375 mg/m(2) per week for 4 consecutive weeks. The drug was well tolerated and complete improvement of arthralgia was immediately evident. There was gradual improvement of lower limbs paresthesia and healing of a leg ulcer that had been active for 5 years. The clinical and immunological responses induced by rituximab are sustained over long-term follow-up, and this case illustrates the drug efficacy for non-responder patients to antiviral therapy.