In registration-based analyses of lung biomechanics and function, high quality registrations are essential to obtain meaningful results. Various criteria have been suggested to find the correspondence mappings between two lung images acquired at different levels of inflation. In this paper, we describe a new metric, the sum of squared vesselness measure difference (SSVMD), that utilizes the rich information of blood vessel locations and matches similar vesselness patterns in two images. Preserving both the lung tissue volume and the vesselness measure, a registration algorithm is developed to minimize the sum of squared tissue volume difference (SSTVD) and SSVMD together. We compare the registration accuracy using SSTVD + SSVMD with that using SSTVD alone by registering lung CT images of three normal human subjects. After adding the new SSVMD metric, the improvement of registration accuracy is observed by landmark error and fissure positioning error analyses. The average values of landmark error and fissure positioning error are reduced by about 30% and 25%, respectively. The mean landmark error is on the order of 1 mm. Statistical testing of landmark errors shows that there is a statistically significant difference between two methods with p values < 0.05 in all three subjects. Visual inspection shows there are obvious accuracy improvements in the lung regions near the thoracic cage after adding SSVMD.© (2010) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.