Surfactant protein A (SP-A) contributes to host defense by opsonizing microbial organisms for phagocytosis by alveolar macrophages (AM). The role of SP-A as opsonin for phagocytosis of Candida albicans was analyzed. AM in suspension exhibited no phagocytosis of nonopsonized yeast. This was not increased by SP-A, whether provided for preincubation of AM or yeast or present during coincubation. However, the engulfment of serum-opsonized yeast by AM in suspension was inhibited by SP-A. This inhibitory effect was mimicked by complement subcomponent C1q and concanavalin A but not by type IV collagen. SP-A did not interfere with phagocytosis of serum-opsonized yeast by adherent AM, monocytes, neutrophils, or peritoneal macrophages. SP-A lacks function as an opsonin for the phagocytosis of C. albicans by AM but interferes with binding of yeast to AM, inhibiting subsequent ingestion. The role of SP-A as an alveolar space opsonin may thus critically depend on the microbial species involved.