Surfactant protein A (SP-A) regulates alveolar macrophage function and has been implicated in the mediation of pulmonary host defense. Our goals were to characterize the interaction of SP-A with various pulmonary pathogens, to investigate the mechanism of SP-A-mediated phagocytosis using an assay that distinguishes bound from internalized bacteria by quenching the fluorescence of extracellular bacteria, and to examine further the interactions of SP-A and the structurally homologous protein complement component 1q (C1q) with alveolar macrophages and peripheral blood monocytes. We found that SP-A binds to and increases the phagocytosis of Haemophilus influenzae, Streptococcus pneumoniae, and Group A Streptococcus; SP-A aggregates only H. influenzae. SP-A neither binds to, aggregates, nor stimulates the phagocytosis of Pseudomonas aeruginosa. We have also found that bronchoalveolar lavage stimulates phagocytosis and that this stimulation is reduced by an anti-SP-A antibody. While the enhancement of phagocytosis by SP-A is inhibited in blood monocytes adhered to C1q-coated surfaces, which presumably clusters the C1q receptor on the basal surface of the cell, alveolar macrophages on C1q-coated slides show no significant change in their response to SP-A. In summary, SP-A stimulates the phagocytosis by alveolar macrophages of specific pulmonary pathogens to which it binds, but aggregation is not required for the effect. Additionally, the role of the C1q receptor in the response to SP-A may differ between monocytes and alveolar macrophages.