Respiratory papillomatosis is a life-spoiling disease due to its high recurrence rate. Interferon (IFN) alpha-2b treatment, adjuvant to surgery, was assessed for its contribution to disease control and patient quality of life improvement. One hundred and sixty-nine patients (85 children and 84 adults) were included after surgical removal of the lesions followed by intramuscular IFN alpha-2b (Heberon alfa R, Heber Biotec), starting with 105 IU/Kg weight in children or 6 × 106 IU in adults, three times per week. The dose was reduced monthly, if no relapses occurred, until a monthly maintenance with 5 × 104 IU/Kg of weight in children or 3 × 106 IU in adults up to two years. In case of relapse, it was surgically removed and the patient returned to the higher dose level. The relapse frequency decreased significantly in 77 per cent (69/90) of the recurrent patients both in children (34/46, 74 per cent) and adults (35/44, 79 per cent). Among patients included after their first papilloma, 67 per cent (44/66) had complete (no relapses) or partial (only one relapse) responses (children: 15/33, 45 per cent; adults 29/33, 88 per cent). One hundred and eighteen patients (73 per cent) concluded the treatment without lesions (children: 58 per cent; adults 82 per cent), while the rest showed a significant reduction in the number and size of lesions. IFN was well tolerated. Sixty-two patients (38 per cent) did not have adverse events. The main adverse reactions were fever (59 per cent), chills (24 per cent), arthralgias and myalgias (14 per cent) and headache (10 per cent). One patient developed anti-IFN alpha neutralizing antibodies and became resistant to treatment with recombinant IFN alpha-2b; he responded to natural leucocyte IFN alpha. Treatment with IFN alpha-2b, as an adjuvant to surgery represents a favourable and safe therapeutic alternative for patients with recurrent respiratory papillomatosis.