The efficacy of systemic interferon-alpha (IFN-alpha n1; Wellferon) treatment on genital human papillomavirus (HPV) infections was studied in a double-blind, placebo-controlled trial. A total of 120 women were randomly allocated to receive either interferon (IFN, n = 60) or placebo (n = 60). In both treatment groups, 15 patients with lesions induced by each of the four HPV types (HPV 6, 11, 16, and 18) were included. The dose of IFN was 1.5 x 10(6) IU subcutaneously three times for the first week followed by 3 x 10(6) IU three times weekly for a further 6 weeks. The control patients received matching placebo injections. Ten patients (three IFN-treated and seven placebo-treated) were lost to follow-up. As determined by colposcopy, cytological and histological examinations, and HPV typing (in situ hybridization, ISH), 8 IFN-treated patients (14%) and 11 placebo-treated patients (18%) showed complete response (CR) at the 8th week. The corresponding figures were 22 (37%) and 25 (43%) at the 24th week and 28 (49%) and 25 (49%) at the 52nd week, respectively. The total number of HPV DNA negative patients at Week 8 was 29 (49%) in the IFN group and 24 (40%) in the placebo group (statistically nonsignificant). At Week 24, 37 (63%) of the IFN-treated patients and 39 (67%) of the placebo-treated patients were HPV DNA negative. In 2 placebo-treated cases, cervical lesions progressed to CIN III and were treated by conization after the 24th week. There were 4 recurrences (7%) in the IFN group and no recurrences in the placebo group at the 24th week, corresponding figures at the 52nd week being 6 (11%) and 4 (7%), respectively. When the clinical efficacy was evaluated in relation to the histological grade of lesion and four different HPV types, there were no differences in CR or in the number of HPV DNA negative patients between the two study groups. In conclusion, systemic IFN-alpha therapy did not show any significant therapeutic effect on genital HPV infections (by HPV types 6, 11, 16, and 18) compared to placebo.