Rationale: Cigarette smoke (CS) exposure is an important risk factor for COPD but not all smokers develop disease, suggesting that other factors influence disease development. Objectives: We sought to determine whether neuropilin-1 (Nrp-1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS. Methods: Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp-1. We determined whether conditional Nrp-1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp-1-deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp-1 silencing on cell death following acute exposure of A549 cells to cigarette smoke extract (CSE) or short chain ceramides. Results: Genetic deletion of epithelial Nrp-1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of Type I and Type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp-1 deficient adult mice. Silencing of Nrp-1 in A549 cells did not alter cell survival after vehicle treatment, but significantly augmented apoptosis following exposure to CSE or ceramide. Conclusions: These data support a role for epithelial Nrp-1 in maintenance of normal alveolar structure, and suggest that dysregulation of Nrp-1 expression may promote epithelial cell death in response to cigarette smoke exposure, thereby enhancing emphysema development.