PurposeWe developed a system for calculating patient positional displacement between digital radiography images (DRs) and digitally reconstructed radiography images (DRRs) to reduce patient radiation exposure, minimize individual differences between radiological technologists in patient positioning, and decrease positioning time. The accuracy of this system at five sites was evaluated with clinical data from cancer patients. The dependence of calculation accuracy on the size of the region of interest (ROI) and initial position was evaluated for clinical use.MethodsFor a preliminary verification, treatment planning and positioning data from eight setup patterns using a head and neck phantom were evaluated. Following this, data from 50 patients with prostate, lung, head and neck, liver, or pancreatic cancer (n = 10 each) were evaluated. Root mean square errors (RMSEs) between the results calculated by our system and the reference positions were assessed. The reference positions were manually determined by two radiological technologists to best‐matching positions with orthogonal DRs and DRRs in six axial directions. The ROI size dependence was evaluated by comparing RMSEs for three different ROI sizes. Additionally, dependence on initial position parameters was evaluated by comparing RMSEs for four position patterns.ResultsFor the phantom study, the average (± standard deviation) translation error was 0.17 ± 0.05, rotation error was 0.17 ± 0.07, and ΔD was 0.14 ± 0.05. Using the optimal ROI size for each patient site, all cases of prostate, lung, and head and neck cancer with initial position parameters of 10 mm or under were acceptable in our tolerance. However, only four liver cancer cases and three pancreatic cancer cases were acceptable, because of low‐reproducibility regions in the ROIs.ConclusionOur system has clinical practicality for prostate, lung, and head and neck cancer cases. Additionally, our findings suggest ROI size dependence in some cases.