Surfactant protein-A (SP-A) gene–targeted mice clear group B streptococcus (GBS) from the lungs at a slower rate than wild-type mice. To determine mechanisms by which SP-A enhances pulmonary clearance of GBS, the role of SP-A in binding and phagocytosis of GBS was assessed in SP-A (−/−) mice infected with GBS in the presence and absence of exogenous SP-A. Coadministration of GBS with exogenous SP-A decreased GBS colony counts in lung homogenates of SP-A (−/−) mice. SP-A bound to GBS in a calcium-dependent manner. Although pulmonary infiltration with macrophages was not altered in SP-A (−/−) versus wild-type mice after GBS infection, the number of alveolar macrophages with phagocytosed bacteria was lower in the SP-A (−/−) mice than in the wild-type mice. When SP-A was coadministered with GBS, phagocytosis was significantly increased. Oxygen radical production by alveolar macrophages from SP-A (−/−) mice infected with GBS was decreased compared with wild-type controls and was increased when SP-A (−/−) mice were infected in the presence of exogenous SP-A. Superoxide (SO) radical generation was deficient in macrophages from SP-A (−/−) mice. SP-A plays an important role in GBS clearance in vivo, mediated in part by binding to and enhancing GBS phagocytosis and by increasing SO production by alveolar macrophages.