Interferon (IFN)-alpha is recognized today as the treatment of choice for chronic hepatitis virus C-related disease. Several factors are able to influence the response to the therapy. In the last few years, several types of IFN-alpha have been used with varying therapeutic results. In order to define the role played by the type of IFN-alpha, as a predictive factor of response to therapy, we studied clinical and biological features of 128 patients (80 males and 48 females, mean age 58.5+/-9.7 years) divided into four homogeneous groups. Four types of IFN-alpha were administered at the same dose and for an identical period. Lymphoblastoid was administered to Group A; recombinant 2a to Group B; recombinant 2b to Group C and leukocyte to Group D. The results showed that the best response was achieved using natural IFN. Statistical evaluation of the predictive factors was carried out using bivariate and multivariate analysis. IFN-alpha was associated with different response rates for viral and biochemical remission at the end of the treatment and at the end of 12 months' follow-up period. Therefore, the type of IFN administered may influence the response to therapy and important independent single predictive factors of response should be taken into account. The type of IFN used may determine how well the disease is controlled.