We examined 12 recurrent respiratory papillomatosis patients, who were undergoing treatment for recurrence of their disease, for the presence of human papillomavirus (HPV). Biopsies were obtained from their respiratory papillomas and nondiseased sites (NDS) of the respiratory tract: the nasopharynx, posterior tonsillar pillar, aryepiglottic fold, cervical trachea, intrathoracic trachea, and bronchi. The presence of HPV DNA was determined by using the ViraPap/ViraType DNA hybridization procedure. Two thirds of the patients were infected with HPV 6/11 in either the diseased papilloma or NDS: 50% of patients with papilloma specimens typed positive (6 of 12), and 40% of the patients typed HPV-positive in one or more biopsies from the NDS (4 of 10). No single NDS was more likely to be infected with HPV than any other. No oncogenic HPV types 16/18 or 31/33/35 were detected in the papillomas or NDS of these patients. Only patients with multiple, and not isolated, papilloma involvement were found to harbor HPV DNA in NDS; and 80% of those with infected NDS, compared to 20% of those without infected NDS, required a shorter (no more than 3 months) surgical treatment interval. Our results show that HPV infection frequently persists in adjacent, clinically normal sites, and suggest that the extent of NDS involvement may predict both the extent of disease and the likelihood of recurrence.