Immunosuppressed Swiss Black mice deficient in surfactant protein A (SP-A^−/−) and wild-type control mice (SP-A^+/+) were exposed to Pneumocystis carinii by environmental exposure, intratracheal inoculation, and direct exposure to other infected animals. The frequency and intensity of P. carinii infection were significantly greater in the SP-A^−/− mice by all 3 methods of exposure. P. carinii free of SP-A and alveolar macrophages were isolated from SP-A^−/− mice and were tested in an in vitro attachment assay. Pretreatment of P. carinii with human SP-A resulted in a significant dose-dependent increase of the adherence of P. carinii to the macrophages. Thus, SP-A plays a role in host defense against P. carinii in vivo, perhaps by functioning as a nonimmune opsonin