Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common β-chain (βc) genes in mice [GM(−/−), βc(−/−)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(−/−) and βc(−/−) mice, surfactant metabolism was compared in βc(−/−), GM(−/−), and wild-type mice. Although lung histology in βc(−/−) and GM(−/−) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant protein concentrations and clearance from lungs of βc(−/−) and GM(−/−) mice. At 1–2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, βc(−/−), and GM(−/−) mice compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing age in βc(−/−) and GM(−/−) mice. Postnatal changes in Sat PC pool sizes were different in GM(−/−) compared with βc(−/−) mice. After 7 days of age, the increased lung Sat PC pool sizes remained constant in βc(−/−) mice but continued to increase in GM(−/−) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percent recovery of [3H]dipalmitoylphosphatidylcholine and125I-recombinant surfactant protein (SP) C was higher in βc(−/−) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect in clearance was significantly more severe in GM(−/−) than in βc(−/−) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoalveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in βc(−/−) and GM(−/−) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concentrations were increased in BALF but not in serum of βc(−/−) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in βc(−/−) and GM(−/−) mice and may provide a molecular basis for the range in severity of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor