Acute lung injury is characterized by heterogeneity of regional mechanical properties, which is thought to be correlated with disease severity. The feasibility of using respiratory input impedance (Z(rs)) and computed tomographic (CT) image registration for assessing parenchymal mechanical heterogeneity was evaluated. In six dogs, measurements of Z(rs) before and after oleic acid injury at various distending pressures were obtained, followed by whole lung CT scans. Each Z(rs) spectrum was fit with a model incorporating variable distributions of regional compliances. CT image pairs at different inflation pressures were matched using an image registration algorithm, from which distributions of regional compliances from the resulting anatomic deformation fields were computed. Under baseline conditions, average model compliance decreased with increasing inflation pressure, reflecting parenchymal stiffening. After lung injury, these average compliances decreased at each pressure, indicating derecruitment, alveolar flooding, or alterations in intrinsic tissue elastance. However, average compliance did not change as inflation pressure increased, consistent with simultaneous recruitment and strain stiffening. Image registration revealed peaked distributions of regional compliances, and that small portions of the lung might undergo relative compression during inflation. The authors conclude that assessments of lung function using Z(rs) combined with the structural alterations inferred from image registration provide unique but complementary information on the mechanical derangements associated with lung injury.