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 bronchoalveolar lavage (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 vs. 30% in SP-D^+/+. The survival advantage in SP-D^−/− mice was accompanied by lower histopathological 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 compared with SP-D^+/+. We conclude that the resistance of SP-D-deficient mice to hyperoxia reflects homeostatic changes in the SP-D^−/− phenotype involving both phospholipid and SP-B-mediated induced resistance of surfactant to inactivation as well as changes in the immunomodulatory BAL cytokine profile.