The clinical use of offline positron emission tomography/computed tomography (PET/CT) scans for proton range verification is currently under investigation at the Massachusetts General Hospital (MGH). Validation is achieved by comparing measured activity distributions, acquired in patients after receiving one fraction of proton irradiation, with corresponding Monte Carlo (MC) simulated distributions. Deviations between measured and simulated activity distributions can either reflect errors during the treatment chain from planning to delivery or they can be caused by various inherent challenges of the offline PET/CT verification method. We performed a systematic analysis to assess the impact of the following aspects on the feasibility and accuracy of the offline PET/CT method: (1) biological washout processes, (2) patient motion, (3) Hounsfield unit (HU) based tissue classification for the simulation of the activity distributions and (4) tumor site specific aspects. It was found that the spatial reproducibility of the measured activity distributions is within 1 mm. However, the feasibility of range verification is restricted to a limited amount of positions and tumor sites. Washout effects introduce discrepancies between the measured and simulated ranges of about 4 mm at positions where the proton beam stops in soft tissue. Motion causes spatial deviations of up to 3 cm between measured and simulated activity distributions in abdominopelvic tumor cases. In these later cases, the MC simulated activity distributions were found to be limited to about 35% accuracy in absolute values and about 2 mm in spatial accuracy depending on the correlativity of HU into the physical and biological parameters of the irradiated tissue. Besides, for further specific tumor locations, the beam arrangement, the limited accuracy of rigid co-registration and organ movements can prevent the success of PET/CT range verification. All the addressed factors explain why the proton beam range can only be verified within an accuracy of 1-2 mm in low-perfused bony structures of head and neck patients for which an accurate co-registration of predominant bony anatomy is possible, as shown previously. However, most of the limitations of the current approach are conquerable. By implementing technological and methodological improvements like the use of in-room PET scanners, PET measurements could soon be used to provide proton range verification in clinical routine.