Circulating lipoproteins are increasingly recognized as innate immune effector molecules. Severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. Importantly, pneumonia caused by Staphylococcus aureus is a major cause of morbidity and mortality in both hospital- and community-acquired pneumonia cases. Here we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing dependent pathogenesis. Specifically, apoB levels in the lung early post-infection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact post-trauma pneumonia susceptibility to both Gram positive and Gram negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung