Recurrent respiratory papillomatosis is a relentless disease of viral origin in which squamous papillomas frequently obstruct the respiratory tract of children and young adults. No therapy has been proved to be curative for this process. Recent reports have suggested that interferon may cure or dramatically control airway papillomatosis. We evaluated the efficacy of human leukocyte interferon in the treatment of respiratory papillomatosis. One hundred twenty-three patients were randomly assigned to receive treatment with either surgery plus interferon or surgery alone. Interferon (2 X 10(6) IU per square meter of body-surface area) was given daily for one week, then three times per week for one year; treatment was followed by a year of observation, without the drug. Both study groups underwent serial endoscopy to remove papillomas and to document the efficacy of treatment during the two years of study. During the first six months, the growth rate of papillomas in the interferon group was significantly lower than in the control group (P = 0.0007). This difference diminished during the second six months and was no longer statistically significant (P = 0.68). Our data do not show that interferon is either curative or of substantial value as an adjunctive agent in the long-term management of recurrent respiratory papillomatosis. The initial benefit of interferon is not sustained.