Rationale: The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly understood. Objectives: These studies seek to implicate a functional role for growth factor VEGF in perpetuating primary nasal epithelial cell overgrowth, a key feature of hyperplastic polyps. Methods: Comparison of VEGF and receptor expression was assessed by ELISA of nasal lavage, immunohistochemistry of sinus tissue, flow cytometry of nasal epithelial cells and ELISA of supernatants. VEGF-dependent cell growth and apoptosis was assessed using blocking antibodies to VEGF, their receptors, or siRNA knockdown of NP1 by cell proliferation assays and flow cytometric binding of annexin V. Results: VEGF protein was 7-fold higher in nasal lavage from polyposis patients compared to controls (p<0.001). We also report elevated expression of VEGF (p<0.012), receptors VEGFR2 and phospho-VEGFR2 (both p<0.04), and identification of VEGF co-receptor neuropilin-1 in these tissues. Nasal epithelial cells from polyp patients demonstrated faster growth rates (p<0.005). Exposure of cells to blocking antibodies against VEGF resulted in inhibition of cell growth (p<0.05). VEGF receptor blockade required blockade of neuropilin-1 (p<0.05) and resulted in increased apoptosis (p<0.001) and inhibition of autocrine epithelial VEGF production (p<0.05). Conclusions: These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed forward manner to promote nasal epithelial cell growth and inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on non-neoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.