A case of hepatitis C virus (HCV)-negative essential mixed cryoglobulinemia with initial skin, joint, and liver involvement, complicated by severe renal and cardiac failure and resistant to corticosteroid therapy, plasmapheresis, chlorambucil, and cyclophosphamide is presented. Treatment with an anti-CD20 monoclonal antibody (rituximab) induced a persistent recovery of renal and cardiac function, disappearance of skin and joint lesions, and disappearance of cryoglobulins. In a 24-month follow-up period, our patient remains in remission and free of symptoms.