Smokers are more susceptible to respiratory viral infections, including influenza virus, yet the mechanisms mediating this effect are not known. To determine how epithelial cells contribute to the enhanced susceptibility seen in smokers, we established an in vitro model of differentiated nasal epithelial cells (NEC) from smokers, which maintained enhanced mucin expression. NEC from smokers responded to influenza infection with greater cytotoxicity, IL-6 release, and viral shedding than NEC from non-smokers. Focusing on type I interferon (IFN) expression, we observed that influenza-infected NEC from smokers produced significantly less IFN-alpha than NEC from non-smokers. Similarly, expression of IRF7, a key transcription factor controlling the expression of IFN-alpha, was significantly decreased in influenza infected and IFN-beta stimulated NEC from smokers. Furthermore, our data indicate that DNA methylation of the IRF7 gene and expression of the DNA (cytosine-5-)-methyltransferase 1 (DNMT1) was enhanced in NEC from smokers. To confirm these findings in vivo, we initiated a study in which smoking and non-smoking healthy volunteers were inoculated nasally with the live-attenuated influenza virus (LAIV) vaccine and nasal biopsies were obtained before and after administration of LAIV. LAIV-induced expression of IRF7 was lower in the nasal epithelium from smokers, supporting our in vitro observations. These data demonstrate that infection with influenza results in reduced expression of the transcription factor IRF7 in NEC from smokers, and that these effects may be mediated by epigenetic modification of the IRF7 gene, thus providing a potential mechanism rendering smokers more susceptible to respiratory virus infections.