Background The Optical Surface Management System (OSMS) is a simple, fast, reproducible, and accurate solution for patient set-up and can minimize random day-to-day set-up errors. However, studies in breast cancer patients are rare. Objective To analyze 200 patient set-ups in 20 patients with breast cancer by comparing the OSMS with the conventional cone-beam computed tomography (CBCT). Method Displacements from concurrent OSMS and CBCT registrations were compared in a total of 200 setups of 20 patients to analyze the interfractional displacement and positioning displacement in three dimensions (lateral, longitudinal, and vertical directions). Results The interfractional displacement on the lateral, longitudinal, and vertical directions for OSMS versus CBCT was 0.049 ± 0.254 versus 0.041 ± 0.244 centimeters (cm); 0.018 ± 0.261 versus 0.040 ± 0.242 cm; 0.062 ± 0.254 versus 0.065 ± 0.240 cm, respectively, without any significant difference (all P > 0.05). The duration for CBCT scan was about 60 seconds (s), while that for image processing, matching, and couch displacement was at least 5 minutes (min). The average scanning time with OSMS was less than 20 s, and the total duration for positioning was less than 1 min. Conclusion OSMS is an efficient tool to improve the accuracy and increase the speed for verifying the patient positioning in radiotherapy for breast cancer.