Pneumocystis carinii is the most common cause oflife-threatening pneumonia in immunocompromised patients. In the current study, surfactant protein A (SP-A), the major nonserum protein constituent of pulmonary surfactant, is demonstrated to bind P. carinii in a specific and saturable manner. SP-A is surface bound and does not appear to be internalized or degraded by the P. carini organism. Furthermore, SP-A binding to P. carini' is time-and calcium-dependent and is competitively inhibited by mannosyl albumin. In the absence of calcium or the presence of excess mannosyl albumin, SP-A binding to P. carinii is reduced by 95 and 71%, respectively. SP-A avidly binds P. carinil with a Kd of8 x 10-9 M and an estimated 8.4 X 106 SP-A binding sites per P. carinii organism, as determined from Scatchard plots. SP-A is shown to bind P. carinli in vivo, and a putative binding site for SP-A on P. carini is demonstrated to be the mannoserich surface membrane glycoprotein gpl20. These findings suggest that P. carinii can interact with the phospholipid-rich material in the alveolar spaces by specifically binding a major protein constituent of pulmonary surfactant. (J. Clin. Invest.