It is well established that exposure to high levels of oxygen (hyperoxia) injures and kills microvascular endothelial and alveolar type I epithelial cells. In contrast, significant death of airway and type II epithelial cells is not observed at mortality, suggesting that these cell types may express genes that protect against oxidative stress and damage. During a search for genes induced by hyperoxia, we previously reported that airway and alveolar type II epithelial cells uniquely express the growth arrest and DNA damage (Gadd) 45a gene. Because Gadd45a has been implicated in protection against genotoxic stress, adult Gadd45-wildtype and deficient mice were exposed to hyperoxia in order to investigate whether it protected epithelial cells against oxidative stress. During hyperoxia, Gadd45-deficiency did not affect loss of airway epithelial expression of CCSP or type II epithelial cell expression of proSP-C. Likewise, Gadd45 deficiency did not alter recruitment of inflammatory cells, edema, or overall mortality. Consistent with Gadd45a not affecting the oxidative stress response, p21^Cip1/WAF1 and heme oxygenase 1 were comparably induced in Gadd45-wildtype and deficient mice. Additionally, Gadd45a deficiency did not affect oxidative DNA damage or apoptosis as assessed by oxidized guanine and TUNEL staining. Over-expression of Gadd45a in human lung adenocarcinoma cells did not affect viability or survival during exposure, while it was protective against UV-radiation. We conclude that increased tolerance of airway and type II epithelial cells to hyperoxia is not attributed solely to expression of Gadd45a.