Vascular endothelial growth factor-A (VEGF-A) is known to play an important role in the angiogenic response essential for tumor growth in a variety of human and experimental tumors. This study was designed to investigate whether VEGF-A may play a role in the pathogenesis of recurrent respiratory papillomatosis (RRP). A retrospective study with institutional review board approval was performed at a tertiary care medical center on 12 patients with a history of laryngeal RRP. Their ages at the time of initial diagnosis ranged from 19 to 96 months (mean, 56 months). All patients had involvement of right and left true vocal cords. All patients required multiple endoscopic procedures (range, 4 to 66; mean, 12). Normal pediatric larynx samples from 5 autopsy patients were used as controls. Formalin-fixed, paraffin-embedded sections of laryngeal squamous papillomas from the 12 patients with a diagnosis of RRP and the 5 control patients were examined by in situ hybridization for the presence of messenger RNA (mRNA) for VEGF-A and vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2). The biopsy specimens were from the true vocal cord (N = 10) or subglottis (N = 2) in the patients with RRP and consisted of large sections of larynx including the true vocal cord in the control patients (N = 5). Strong expression of VEGF-A mRNA was noted in the squamous epithelium of papillomas of all 12 patients. Strong expression of VEGFR-1 and VEGFR-2 was noted in the endothelial cells of the underlying vessels in all 12 patients. Neither strong labeling of VEGF-A mRNA nor labeling of its receptors wasnoted in the control patients. We conclude that the angiogenic growth factor VEGF-A is strongly expressed in the epithelium of squamous papillomas in RRP. Also, VEGFR-1 and VEGFR-2 mRNAs are strongly expressed by underlying vascular endothelial cells, suggesting an important role in the pathogenesis of RRP.