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Several authors have reported on the effectiveness of alpha-interferon (IFN-alpha) in the treatment of patients with mixed cryoglobulinemia. This prompted the authors to investigate the long term effects of this drug on clinical, hematologic, and virologic parameters in a group of 20 patients (13 women and 7 men) affected by mixed cryoglobulinemia.In all patients, bone marrow biopsy, phenotyping of marrow cells, and polymerase chain reaction (PCR) immunoglobulin gene rearrangement in peripheral blood lymphocytes were performed before therapy and at the end of the follow-up. A liver biopsy was obtained in patients with biochemical signs of chronic liver disease. The presence of hepatitis C virus (HCV) RNA in serum was assessed by detection of anti-HCV antibodies, and by PCR amplification of the 5' untranslated region of HCV. The HCV genotype was also determined by PCR amplification of the core region of the virus with type-specific primers. The treatment schedule followed by all patients was 3 million units of recombinant IFN-alpha 2b 3 times weekly for 1 year.In 6 patients, the marrow histology before therapy showed a massive (more than 50%) monomorphous infiltration by plasmacytoid lymphocytes, indicating the presence of low grade non-Hodgkin's lymphoma. Anti-HCV antibodies were present in 19 (95%) subjects, and HCV-RNA was detectable in all patients. In addition, all patients affected by Type II mixed cryoglobulinemia showed a monoclonal B-cell expansion in peripheral blood mononuclear cells (PBMC). With therapy, 5 patients (25%) achieved a complete response and 11 patients (55%) a partial response, whereas minor responses were observed in the remaining 4 patients (20%). One of the complete responders and all patients showing partial responses relapsed a few months after therapy withdrawal. At the end of the follow-up, four patients had obtained a complete remission. Bone marrow examination showed that B-lymphocytic monoclonal infiltrate disappeared in three patients. Moreover, these three patients had become negative for B-cell expansion in PBMC. Lack of response, or relapse, was associated with the presence of Type II HCV.HCV may be the cause of mixed cryoglobulinemia. The disease is associated with a high prevalence of bone marrow B-cell lymphomas. IFN-alpha appears to be an effective agent for the treatment of mixed cryoglobulinemia. It also seems able to determine regression of the lymphoproliferative disorder. The HCV genotype appears to be the most important predictive factor for the response to antiviral therapy.