Severe influenza virus-induced disease is characterised by acute lung injury, associated with a vigorous inflammatory response. However, disease severity varies between individuals and this cannot be entirely explained by differences in influenza strain virulence, or an individual’s pre-existing adaptive immunity or health status. Host specific genetic factors must therefore contribute to susceptibility. Type I interferon (IFNαβ) is known to have antiviral function in-vitro, yet its role in influenza infection in-vivo is less clear. Aims: To identify host specific determinants of susceptibility to influenza-induced disease. Methods: We assessed susceptibility of inbred mouse strains to influenza-induced disease where viral load was comparable during early infection. Influenza-induced gene expression, cytokine production and cellular recruitment, activation and death in the pulmonary environment were compared between susceptible and resistant mouse strains. Results: Influenza infected 129 and DBA strains showed dramatically increased morbidity, mortality and lung damage, yet higher levels of pulmonary IFNαβ, compared to the more resistant C57BL/6 or BALB/C mice. Ablation of IFNαβR signalling in 129 mice markedly reduced mortality, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells such as inflammatory monocytes (IMs). Furthermore, IFNα treatment of influenza-infected C57BL/6 mice increased morbidity. Plasmacytoid dendritic cells (pDCs), which are potent IFN producers, were recruited in higher numbers to lungs of infected 129 mice. pDC derived IFNαβ was demonstrated to be upstream of the robust proinflammatory response. Significantly, IFNαβ signalling induced the upregulation of Tumour necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) on IMs and its receptor: Death Receptor 5 (DR5) on lung epithelia. TRAIL-DR5 interaction is required for epithelial apoptosis, lung damage and mortality of 129 mice. Conclusion: Host-intrinsic differences can determine the severity of influenza-induced disease. pDC frequency and responsiveness to IFNαβ signalling is a host-specific determinant with protective or pathogenic potential. This study has important implications for the prediction and treatment of severe influenza-induced disease.