Resident immune cells (e.g., macrophages [MFs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MF function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MF depletion was generated, characterized, and crossed with the sodium channel b subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM 1 pulmonary MFs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM 1 MF depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM 1 MF-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM 1 MF-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM 1 MF-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MF-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease.