PURPOSE: Four-dimensional positron emission tomography (4D PET) imaging of the thorax produces sharper images with reduced motion artifacts. Current radiation therapy planning systems, however, do not facilitate 4D plan optimization. When images are acquired in a 2-minute time slot, the signal-to-noise ratio of each 4D frame is low, compromising image quality. The purpose of this study was to implement and evaluate the construction of mid-position 3D PET scans, with motion compensated using a 4D computed tomography (CT)-derived motion model. METHODS AND MATERIALS: All voxels of 4D PET were registered to the time-averaged position by using a motion model derived from the 4D CT frames. After the registration the scans were summed, resulting in a motion-compensated 3D mid-position PET scan. The method was tested with a phantom dataset as well as data from 27 lung cancer patients. RESULTS: PET motion compensation using a CT-based motion model improved image quality of both phantoms and patients in terms of increased maximum SUV (SUV(max)) values and decreased apparent volumes. In homogenous phantom data, a strong relationship was found between the amplitude-to-diameter ratio and the effects of the method. In heterogeneous patient data, the effect correlated better with the motion amplitude. In case of large amplitudes, motion compensation may increase SUV(max) up to 25% and reduce the diameter of the 50% SUV(max) volume by 10%. CONCLUSIONS: 4D CT-based motion-compensated mid-position PET scans provide improved quantitative data in terms of uptake values and volumes at the time-averaged position, thereby facilitating more accurate radiation therapy treatment planning of pulmonary lesions.