Metabolism of surfactant protein (SP) A and dipalmitoylphosphatidylcholine (DPPC) was assessed in alveolar macrophages isolated from granulocyte-macrophage colony-stimulated factor (GM-CSF) gene-targeted [GM(−/−)] mice, wild-type mice, and GM(−/−) mice expressing GM-CSF under control of the SP-C promoter element (SP-C-GM). Although binding and uptake of ¹²⁵I-SP-A were significantly increased in alveolar macrophages from GM(−/−) compared with wild type or SP-C-GM mice, catabolism of¹²⁵I-SP-A was markedly decreased in GM(−/−) mice. Association of [³H]DPPC with alveolar macrophages from GM(−/−), wild-type, and SP-C-GM mice was similar; however, catabolism of DPPC was markedly reduced in cells from GM(−/−) mice. Fluorescence-activated cell sorter analysis demonstrated decreased catabolism of rhodamine-labeled dipalmitoylphosphatidylethanolamine by alveolar macrophages from GM(−/−) mice. GM-CSF deficiency was associated with increased SP-A uptake by alveolar macrophages but with impaired surfactant lipid and SP-A degradation. These findings demonstrate the important role of GM-CSF in the regulation of alveolar macrophage lipid and SP-A catabolism.