Attachment of Mycobacterium tuberculosis organisms to alveolar macrophages (AMs) is an essential early event in primary pulmonary tuberculosis. Surfactant protein A (SP-A) is a nonimmune opsonin present in the alveolar spaces that binds carbohydrate residues such as mannose. It was hypothesized that SP-A attaches to M. tuberculosis and serves as a ligand between M. tuberculosis and AMs. [¹²⁵I]SP-A was found to bind to M. tuberculosis in a time- and [Ca²⁺]-dependent manner with a K _d of 1.9 × 10⁻⁹ M and an apparent number of 6.3 × 10² SP-A binding sites/organism. Further, deglycosylated SP-A had minimal binding to M. tuberculosis, indicating that sugar moieties are important in this interaction. SP-A  specifically binds to a 60-kD cell-wall protein from M. tuberculosis. SP-A-mediated attachment of ⁵¹Cr- labeled M. tuberculosis organisms to AMs is dependent on time, SP-A concentration, and Ca²⁺. M. tuberculosis attachment to murine AMs in the absence of SP-A was 12.8 ± 0.9%; however, in the presence of 5 μg/ml SP-A the attachment increased to 38.6 ± 2.9% (P < 0.001). SP-A-mediated attachment was significantly decreased from 38.6 ± 2.9% to 18.7 ± 3.3% (P < 0.05) in the presence of antihuman SP-A antibodies. When the attachment assay was repeated in the presence of α-methylene-D-mannosepyranosidase (mannosyl–BSA) and type V collagen, SP-A-mediated attachment decreased from 38.6 ± 2.9% to 16.6 ± 1.5% (P < 0.001) and 19.1 ± 1.4% (P < 0.05), respectively. Further, deglycosylated SP-A had only a minimal effect on M. tuberculosis attachment to AMs. These data indicate that SP-A can mediate M. tuberculosis attachment to AMs, and suggest possible underlying mechanisms for this.