Positivity of rheumatoid factor (RF) in the course of Hepatitis C virus HCV infection has been described in many papers, with percentages between 30% and 80%, but no data are reported on the behaviour of this parameter during the treatment. In the present retrospective study, 66 patients with HCV infection and positivity for RF were observed between March 2001 and January 2004; they had received combined therapy with Peg-IFN alpha-2b 1.5 mcg/kg/weekly and ribavirin 800-1200 mg/daily (on the basis of body weight). Before treatment, all of them had presented hypertransaminasemia for at least 6 months and high viral load. No patient suffered from other hypersensitivity disorders. The follow-up period lasted for a mean period of 26+/-7 months, after which only 34 (51.5%) revealed normal transaminases activity with negativity of HCV-RNA (long-term responders, LTR), while the remaining 32 (48.5%) were classified as non responders (NR). In both groups significant variations of RF values were observed. Moreover, RF remained positive in 6 (17.6%) of the LTR group and in 17 (53.1%) of the NR group patients. These data suggest a possible inhibiting action of the combined therapy on the exaggerated immune response. This effect appears partially unrelated to the antiviral action of the therapy.