Influenza is an acute respiratory disease that can cause local annual epidemics and worldwide pandemics of different morbidity and mortality. Our understanding of host factors that modulate the frequency and severity of influenza virus infections is less than complete. In this study, we examined the inter-individual variations in the innate immune responses to H1N1 and H3N2 influenza A viruses (IAV) using primary cultures of normal human bronchial epithelial (NHBE) cells derived from two different donors (D1 and D2). Although IAV replication kinetics were similar in cultures derived from these two donors, the levels of type III interferons (IFNs) were significantly higher in D1 cells compared to D2 cells (?31-fold↑ in D1 cells versus D2 cells; P < 0.05). The levels of IFN-λ1 protein at individual time points as well as the total amounts of IFN-λ1 secreted over 72?h were also significantly higher in D1 than in D2 NHBE cells (0.7-7.7-fold↑, P < 0.05). The relative levels of IFN-stimulated gene (ISG) expression also differed significantly between D1 and D2 cells. Our data indicate that donor-specific differences can result in significant differences in IFN and ISG induction by human airway epithelium.