Interferon-alpha (IFN-alpha) has become an important drug for the treatment of chronic viral liver diseases. However, the action of IFN-alpha remains unclear. We investigated whether human recombinant IFN-alpha modulates serum concentrations of hyaluronic acid (HA) and type III procollagen aminoterminal propeptide (P-III-NP) in 56 patients with chronic hepatitis-B under IFN-alpha therapy. IFN-alpha increased the HA serum level in 44 of 46 patients and, after cessation of treatment, HA serum levels returned to the pretherapy levels. The increase of HA serum level was higher in patients with active cirrhosis (aC) than in patients with chronic persistent hepatitis (CPH) and in patients with severe inflammation compared to those with moderate inflammation. Interestingly, HA serum concentration was unrelated to IFN dose and was of no predictive value for therapy response. In contrast, IFN-alpha increased significantly the P-III-NP serum level in patients with aC only. During follow-up, P-III-NP serum level decreased late in responders in parallel to the decrease of serum level of liver enzymes, in non-responders it was without significant change. The first dose of IFN induced a significant increase in HA serum level in each of 10 patients but in none of four healthy volunteers. In contrast, P-III-NP serum concentrations were not influenced by the first IFN-alpha dose. We conclude that: (1) immunstimulation with IFN-alpha induces a rapid increase of HA serum level in patients with chronic hepatitis B but not in normal persons; (2) IFN-alpha increases P-III-NP serum level only in patients with active liver cirrhosis; (3) measurement of HA and P-III-NP serum levels does not help predict response to IFN-alpha, and (4) HA serum level may be used as a compliance indicator.