To investigate the activity of parenterally administered interferon-beta (IFN-beta) in women with genital human papillomavirus (HPV) infection, serum 2'-5'-oligoadenylate synthetase (2'-5'OAS), an enzyme induced by IFNs, was measured before, during, and after therapy. Serum levels of 2'-5'OAS significantly increased during therapy (P = .005). The patients classified as not responding to treatment at 3 months of follow-up had baseline levels of 2'-5'OAS significantly higher than those who responded to treatment (P = .0011). Differences between the IFN-beta-treated group and untreated controls appeared at day 6 (P = .0019). 2'-5'OAS is a useful parameter in monitoring parenterally administered IFN-beta. The data suggest that women with genital HPV infection and elevated baseline levels of 2'-5'OAS are unlikely to respond to therapy with IFN-beta.