Surfactant protein (SP)-A and SP-D, members of the collectin family, are involved in innate host defenses against various bacterial and viral pathogens. In this study, we asked whether SP-A and SP-D enhance clearance of a nonmucoid strain of Pseudomonas aeruginosa from the lungs. We infected mice deficient in SP-A (SP-A-/-), SP-D (SP-D-/-) and both pulmonary collectins (SP-AD-/-) by intratracheal administration of P. aeruginosa. Six hours after infection, bacterial counts were significantly higher in SP-A-/-, SP-D-/-, and SP-AD-/- compared with wild-type (WT) mice. Forty-eight hours after infection, bacterial counts were significantly higher in SP-A-/- mice compared with WT mice and in SP-AD-/- mice compared with WT, SP-A-/-, and SP-D-/- mice. Phagocytosis of the bacteria by alveolar macrophages was decreased in SP-A-/- and SP-D-/- mice. Levels of macrophage inflammatory peptide-2 and IL-6 were more elevated in the lungs of SP-D and SP-AD-/- mice compared with WT mice. There was more infiltration by neutrophils in the lungs of SP-D-/- compared with WT and SP-A-/- mice 48 h after infection. This study shows that SP-A and SP-D enhance pulmonary clearance of P. aeruginosa by stimulating phagocytosis by alveolar macrophages and by modulating the inflammatory response in the lungs. These findings also show that the functions of SP-A and SP-D are not completely redundant in vivo.