Purpose To perform lung image registration for reducing misregistration artifacts on three-dimensional (3D) temporal subtraction of chest computed tomography (CT) images, in order to enhance temporal changes in lung lesions and evaluate these changes after deformable image registration (DIR). Methods In 10 cases, mutual information (MI) lung mask affine mapping combined with cross-correlation (CC) lung diffeomorphic mapping was used to implement lung volume registration. With advanced normalization tools (ANTs), we used greedy symmetric normalization (greedy SyN) as a transformation model, which involved MI-CC-SyN implementation. The resulting displacement fields were applied to warp the previous (moving) image, which was subsequently subtracted from the current (fixed) image to obtain the lung subtraction image. Results The average minimum and maximum log-Jacobians were 0.31 and 3.74, respectively. When considering 3D landmark distance, the root-mean-square error changed from an average of 20.82 mm for Pfixed to Pmoving to 0.5 mm for Pwarped to Pfixed. Clear shadows were observed as enhanced lung nodules and lesions in subtraction images. The lesion shadows showed lesion shrinkage changes over time. Lesion tissue morphology was maintained after DIR. Conclusions DIR (greedy SyN) effectively and accurately enhanced temporal changes in chest CT images and decreased misregistration artifacts in temporal subtraction images.