Surfactant Protein D (SP-D), a member of the collectin superfamily, modulates pulmonary inflammatory responses and innate immunity. Disruption of the SP-D gene in mice induces peribronchiolar inflammation, accumulation of large, foamy macrophages, increased BAL phospholipid and pulmonary emphysema. We hypothesized that absence of SP-D aggravates hyperoxia-induced injury. To test this, SP-D deficient (SP-D^-/-) and wild type (SP-D^+/+) mice were exposed to 80% or 21% oxygen. Paradoxically, during 14 days of hyperoxia, SP-D^-/- mice had 100% survival versus 30% in SP-D^+/+. The survival advantage in SP-D-/- mice was accompanied by lower histopathologic injury scores at days 5 and 14, although total BAL cells (8.2 ± 1.4 *10⁵ in SP-D^-/- vs. 4.04 ± 0.25 *10⁵ in SP-D^+/+ mice), and neutrophils (1.2 ± 0.4 *10⁵ vs. 0.03 ± 0.02 *10⁵ in SP-D^-/- and SP-D^+/+ respectively) were increased. In addition, BAL protein and lung to body weight ratios were similarly elevated in both groups after 3, 5 and 14 days of continuous exposure. Biochemically, in contrast to SP-D^+/+, SP-D^-/- mice had higher levels of surfactant phospholipid and SP-B at baseline and 5 days after hyperoxia accompanied by a preservation of surfactant biophysical activity. From a multiplex assay of nine cytokines, we found elevated levels of IL-13 in BAL fluid of normoxic SP-D^-/- mice as compared to SP-D^+/+. We conclude that the resistance of SP-D deficient mice to hyperoxia reflects homeostatic changes in the SP-D^-/- phenotype involving phospholipid and SP-B mediated resistance of surfactant to inactivation as well as changes the immunomodulatory BAL cytokine profile.