Defective efferocytosis in the airway may perpetuate inflammation in smokers with/without COPD. Mannose binding lectin (MBL) improves efferocytosis in vitro; however, the effects of in vivo administration are unknown. MBL circulates in complex with MBL-associated serine proteases (MASPs), and efferocytosis involves activation of cytoskeletal-remodeling molecules including Rac1/2/3. We hypothesized that MBL would improve efferocytosis in vivo and that possible mechanisms for this effect would include upregulation of Rac1/2/3 or MASPs. We utilized a smoking mouse model to investigate the effects of MBL on efferocytosis. MBL (20µg/20g mouse) was administered via nebulizer to smoke-exposed mice. In lung tissue (disaggregated) and BAL we investigated leukocyte counts, apoptosis, and the ability of alveolar and tissue macrophages to phagocytose apoptotic murine epithelial cells. In human studies, flow cytometry, ELISA and RT-PCR were used to investigate the effects of MBL on efferocytosis, Rac1/2/3 and MASPs. Smoke exposed mice showed significantly reduced efferocytosis in BAL and tissue. Efferocytosis was significantly improved by MBL (BAL:control 26.2%, smoke-exposed 17.66%, MBL +smoke-exposed 27.8%; Tissue:control 35.9%, smoke-exposed 21.6%, MBL +smoke-exposed 34.5%). Leukocyte/macrophage counts were normalized in smoke-exposed mice treated with MBL. In human studies, MBL was reduced in COPD and smokers and significantly correlated with reduced efferocytosis ex vivo. MASPs were not detected in BAL and not produced by alveolar or tissue macrophages. MBL significantly increased macrophage expression of Rac1/2/3. We provide evidence for Rac1/2/3 involvement in the MBL-mediated improvement in efferocytosis and a rationale for investigating MBL as a supplement to existing therapies in smoking-related lung inflammation.