Hyperoxia is an important cause of acute lung injury. To determine whether IL-13 is protective in hyperoxia, we compared the survival in 100% O₂ of transgenic mice that overexpress IL-13 in the lung and of nontransgenic littermate controls. IL-13 enhanced survival in 100% O₂. One hundred percent of nontransgenic mice died in 4–5 days, whereas 100% of IL-13–overexpressing mice lived for more than 7 days, and many lived 10–14 days. IL-13 also stimulated VEGF accumulation in mice breathing room air, and it interacted with 100% ₂ to increase VEGF accumulation further. The 164–amino acid isoform was the major VEGF moiety in bronchoalveolar lavage from transgenic mice in room air, whereas the 120– and 188–amino acid isoforms accumulated in these mice during hyperoxia. In addition, antibody neutralization of VEGF decreased the survival of IL-13–overexpressing mice in 100% ₂. These studies demonstrate that IL-13 has protective effects in hyperoxic acute lung injury. They also demonstrate that IL-13, alone and in combination with 100% ₂, stimulates pulmonary VEGF accumulation, that this stimulation is isoform-specific, and that the protective effects of IL-13 are mediated, in part, by VEGF.