We report the results of a clinical study using Indole-3-Carbinol (I3C) for the treatment of recurrent respiratory papillomatosis (RRP). I3C is abundant in cruciferous vegetables and has been shown to decrease papillomatous growth in cell cultures and be effective in an animal model of RRP. This is a prospective, open-label study design. Patients with RRP were enrolled from September 1996 to August 2001 and treated with I3C (adult dose of 200 mg PO BID). All patients underwent complete surgical removal and then started I3C. Further surgery was performed on an as-needed basis. Patients were categorized as having a complete, partial, or no response to I3C. Thirty-three patients treated with I3C were available for long-term follow-up (mean=4.8 years), whereas 12 patients were lost to follow-up. Eleven (33%) patients experienced remission of papillomatous growth and did not require surgery while on I3C. Ten (30%) patients had a reduction in papillomatous growth that resulted in less frequent surgery. Twelve patients (36%) had no clinical response. No patients experienced a worsening of their RRP. Of the 9 pediatric patients available, 1 experienced a complete response, 3 a partial response, and 5 had no response to I3C. Twelve patients with a positive response (partial or complete) to I3C are still taking I3C. Seven positive responders discontinued I3C, 3 of which have remained disease-free, whereas 4 continue to have RRP. No immediate or long-term side effects related to I3C were found. I3C has been found to be a successful treatment option for RRP. I3C's efficacy in pediatric patients merits further study.