Since a striking association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia has been demonstrated, the aim of this study is to investigate the effect of alpha-interferon (alpha-IFN) on HCV viraemia and clinico-serological manifestations of 15 patients (ten female and five male, mean [+/- SD] age 53 +/- 7 years). In 14/15 patients pre-study steroid dosage remained unchanged during treatment. alpha-IFN was administered at a dose of 2 x 10(6) IU daily for a month, then every other day for five months. On the whole, a statistically significant improvement of purpura (p < 0.001), serum transaminases (p < 0.001), and cryocrit (p < 0.01) was observed after alpha-IFN treatment. HCV viraemia was detected by polymerase chain reaction technique in 13/15 patients with mixed cryoglobulinemia and anti-GOR antibodies, expression of HCV-related autoimmunity, were present in 8/15. After alpha-IFN treatment, HCV RNA levels showed a clear-cut reduction in five persons and disappeared in another, while anti-HCV antibodies (Chiron ELISA and RIBA II) did not change after the six-month period of therapy. These data further support the possible etiopathogenetic role of HCV in patients with mixed cryoglobulinemia and suggest that alpha-IFN may be regarded as the elective treatment in this disease.