ABSTRACT— It was our aim to evaluate whether the baseline activity of 2–5 oligoadenylate synthetase (2–5 OAS) in serum and changes induced by the treatment with interferon are relevant factors in remission of chronic hepatitis C. Seventeen out of 30 adult patients with chronic hepatitis C were randomized to receive recombinant alpha-2b interferon at the dosage of 3 MU three times weekly. By the end of the third month, nine patients had normalized transaminase levels and continued to receive 3 MU of interferon for an additional 3 months, whereas in eight non-responders the dosage was increased to 6 MU for the same period of time. A single patient responded to the increased dosage. Baseline 2–5 OAS serum activity was significantly higher in patients with chronic hepatitis when compared with normal controls. Follow-up on the 13 untreated cases showed that 2–5 OAS elevation was stable and unrelated to concomitant infections. Comparison of responders and non-responders showed that the latter had higher baseline 2–5 OAS activity, tended to have an earlier and higher peak in the enzyme during the first 4 weeks of treatment, and maintained higher levels during the first 3 months of therapy. The increased dosage of interferon in this group led to an additional, although temporary, increase in 2–5 OAS. Our data suggest that HCV infection by itself induces elevated 2–5 OAS levels. The paradoxical increase in non-responders indicates that monitoring of the enzyme in serum does not predict the response to interferon. The role of the 2–5 OAS pathway in inducing the antiviral state in HCV infection should be further evaluated at tissue level.