The main function of the respiratory system is gas exchange. Since many disease or injury conditions can cause biomechanical or material property changes that can alter lung function, there is a great interest in measuring regional lung ventilation and regional specific volume change. We describe a registration-based technique for estimating local lung expansion from multiple respiratory-gated CT images of the thorax. The degree of regional lung expansion is measured using the Jacobian (a function of local partial derivatives) of the registration displacement field, which we show is directly related to specific volume change. We compare the ventral–dorsal patterns of lung expansion estimated across five pressure changes to a xenon CT based measure of specific ventilation in five anesthetized sheep studied in the supine orientation. Using 3D image registration to match images acquired at 10 cm Symbol and 15 cm Symbol airway pressures gave the best match between the average Jacobian and the xenon CT specific ventilation (linear regression, average Symbol).