The relative contributions of the hydrophilic surfactant proteins (SP)-A and D to early inflammatory responses associated with lung dysfunction after experimental allogeneic hematopoietic stem cell transplantation (HSCT) were investigated. We hypothesized that the absence of SP-A and SP-D would exaggerate allogeneic T cell-dependent inflammation and exacerbate lung injury. Wild type, SP-D-deficient (SP-D^-/-), and SP-A and D double knockout mice (SP-A/D^-/-) C57BL/6 mice were lethally conditioned with cyclophosphamide and total body irradiation and given allogeneic bone marrow plus donor spleen T cells, simulating clinical HSCT regimens. On day 7 after HSCT, permeability edema progressively increased in SP-D^-/- and SP-A/D^-/- mice. Allogeneic T cell-dependent inflammatory responses were also increased in SP-D^-/- and SP-A/D^-/- mice, but the altered mediators of inflammation were not identical. Compared to wild type, bronchoalveolar lavage fluids (BALF) levels of nitrite plus nitrate, GM-CSF, and MCP-1, but not TNF- and IFN-, were higher in SP-D-deficient mice before and after HSCT. In SP-A/D^-/- mice, day 7 post-HSCT BALF levels of TNF-, and IFN-, in addition to nitrite plus nitrate and MCP-1, were higher compared to mice lacking SP-D alone. After HSCT, both SP-A and SP-D exhibit anti-inflammatory lung protective functions that are not completely redundant in vivo.