Rapid removal of apoptotic cells is an important mechanism for immune homeostasis and the resolution of inflammation. Delayed clearance of apoptotic alveolar macrophages may cause activation of healthy bystander macrophages and contribute to high macrophage number and emphysema in surfactant protein D (SP-D) knock-out mice. Using flow cytometry and Annexin V and propidium iodide as markers for apoptosis and necrosis, respectively, SP-D-deficient mice were found to have a 5- to 10-fold increase in the number of apoptotic and necrotic alveolar macrophages in the lungs. SP-D-deficient mice accumulate apoptotic macrophages in the lung, and this accumulation can be reduced by treatment with recombinant SP-D (but not SP-A). The recombinant SP-D binds preferentially to apoptotic cells. The data are consistent with a specific role in vivo for SP-D in promoting apoptotic cell clearance in the lungs to limit macrophage-mediated inflammation and reveal a potential new mechanism for therapeutic targeting in the prevention of emphysema.