The purpose of this study was to evaluate adjuvant drug therapies combined with standard laser excision in the treatment of recurrent respiratory papillomatosis. Previous studies have presented conflicting data on the efficacy of various treatments, including interferon and isotretinoin. A retrospective study of 34 patients with moderate to severe papillomatosis who underwent both laser surgery and adjuvant therapy was therefore performed. All patients were treated with interferon. Five interferon failures received isotretinoin, and three with recalcitrant disease received methotrexate. Interferon produced a complete response in 16 patients and partial response in 12 patients. Juvenile-onset disease had a slightly higher response to interferon than adult-onset disease. isotretinoin produced no response in all five patients. Methotrexate demonstrated a marked improvement in both severity of disease and treatment interval in all three patients. Serious side effects were limited to one interferon patient with febrile seizures, which resolved with discontinuation of therapy. We conclude that adjuvant therapy including interferon and methotrexate is clearly of benefit in the treatment of patients with respiratory papillomatosis. A detailed approach to surgery combined with an interferon dosing regimen is presented. Further study of methotrexate appears warranted.