In these studies we determined if progressive pulmonary inflammation associated with aging in surfactant protein-D (Sftpd)-/- mice leads to an exacerbated response to ozone. In Sftpd-/- mice, but not WT mice, increasing age from 8 wk to 80 wk was associated with increasing numbers of enlarged vacuolated macrophages in the lung, along with alveolar wall rupture and increased bronchoalveolar lavage protein and cells, as well as Type II hyperplasia. In Sftpd-/- mice, heme oxygenase+ macrophages also increased with age, together with classically (iNOS+) and alternatively (mannose receptor+, YM-1+, or galectin-3+) activated macrophages. In WT and Sftpd-/- mice, increasing age from 8 wk to 27 wk resulted in reduced lung stiffness, as reflected by decreases in resistance and elastance spectra. This response was blunted in 80 wk old Sftpd-/- mice. Ozone exposure (0.8 ppm, 3 h) caused increases in lung pathology, alveolar epithelial barrier dysfunction, and numbers of iNOS+ macrophages in 8 wk and 27 wk old Sftpd-/-, but not WT mice. Conversely, while increases in alternatively activated macrophages were observed in 8 wk old WT mice following ozone exposure, no changes were observed in Sftpd-/- mice. Ozone also caused alterations in both airway and tissue mechanics in Sftpd-/- mice at 8 wk and 27 wk, but not at 80 wk. These data demonstrate that mild to moderate pulmonary inflammation results in increased sensitivity to ozone; however, in senescent mice, these responses are overwhelmed by the larger effects of age-related increases in baseline inflammation and lung injury.