Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 (IL-1) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1-induced lung injury in the newborn, we compared the effects of IL-1 on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 with wild-type (IL-1/MMP-9+/+) or null (IL-1/MMP-9-/-) MMP-9 loci. IL-1 increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9+/+ mice. IL-1/MMP-9-/- mice had fewer neutrophils but more macrophages in the lungs than IL-1/MMP-9+/+ mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1-expressing mice. IL-1/MMP-9-/- mice had more severe alveolar hypoplasia than IL-1/MMP-9+/+ mice, implying that IL-1-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.