Methicillin resistant Staphylococcus aureus (MRSA) is epidemic in the United States and is a leading cause of pneumonia. It is capable of activating the type I and III interferon pathways. Intranasal infection of Ifnlr-/- mice with S. aureus led to significantly improved bacterial clearance from the airway (95%) and lung tissue (99%) (P<0.001) compared to WT mice following a 24-hour infection. In a mortality model of infection Ifnlr-/- mice survived, whereas 75% of WT mice succumbed to infection (P<0.05). Despite lack of differences in recruitment of immune cells to the airway in Ifnlr-/- mice, differences were observed in surface marker expression. Ly6C and Ly6G expression was higher on neutrophils and CD200R and MARCO expression was higher on alveolar macrophages from Ifnlr-/- infected mice when compared to WT infected, indicating a potentially important role for these cells in bacterial clearance and in the regulation of inflammation. Interestingly, intracellular staining for IFN λ showed that the production of this cytokine is highly induced in alveolar macrophages after a 24h infection with S. aureus in WT mice (p<0.005). Analysis of bronchoalveolar lavage fluid from WT and Ifnlr-/- infected mice showed significant reductions in several proinflammatory cytokines after 24h of infection, notably IL-1β, which was decreased by 97% (P<0.001) in Ifnlr-/- infected mice and was reduced by 75% (P<0.0001) 4h after infection. We examined inflammasome activation in mice lacking NLRP3 and caspase-1 and still observed production of IL-1β 24 h after infection. Casp1-/- infected mice did display reduced IL-1β after 4h of S. aureus infection. These results suggest that in S. aureus pneumonia, NLRP3 contributes minimally to IL-1β production and caspase-1 is important early before other IL-1β converting proteases are active. Our data suggests that type III IFN signalling might be involved in modulation/regulation of IL-1β levels in response to S. aureus.