Interferon-β (IFNβ) is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFNβ for post-septic ARDS to better understand its pathogenesis in mice. Post-septic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFNβ 1 day earlier. Sepsis induced prolonged increases in alveolar tumor necrosis factor (TNF)α and interleukin (IL)-10 levels and innate immune reprograming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNFα or IL-10 duplicated cytokine-release impairment. Pneumonia following sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli, despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality, compared with sepsis or pneumonia alone. Importantly, IFNβ reversed the TNFα/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment, bacterial clearance, and consequently reduced the odds ratio (OR) for 7-day mortality by 85% (OR, 0.15 [95% confidence interval 0.03-0.82]; p=0.045). This mouse model of sequential sepsis→pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for post-septic ARDS, and systemic IFNβ improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.