To evaluate the setup accuracy of surface-guided radiation therapy (SGRT) compared with traditional skin marks in patients undergoing hypofractionated whole breast irradiation, with a specific focus on our institution's practice of full eliminating skin marks from the computed tomography (CT) simulation. We retrospectively reviewed 184 breast cancer patients treated with hypofractionated whole breast irradiation between January 2022 and May 2023. Initial patient positioning was performed using either traditional skin marks (n = 93, 1488 sessions) or surface-guidance technology via AlignRT (n = 91, 1456 sessions). The setup accuracy was evaluated by analyzing translational couch shifts in vertical, longitudinal, and lateral directions through daily verification using orthogonal kV images in anterior-posterior and lateral directions obtained after initial positioning. The time from initial patient positioning to treatment was also compared. The average translational couch shifts after initial positioning with skin marks were 3.2 ± 1.8 mm, 3.3 ± 1.5 mm, and 2.8 ± 1.4 mm in the vertical, longitudinal, and lateral directions, respectively. For SGRT, the average translational couch shifts were 3.5 ± 1.5 mm, 3.3 ± 1.4 mm, and 2.8 ± 1.2 mm, respectively. There were no significant differences between SGRT and skin marks in any direction. The average time from initial patient positioning to treatment was shorter in patients with SGRT compared to those with skin marks, 261 s vs. 281 s. The elimination of skin marks from the CT simulation stage, facilitated by SGRT, resulted in comparable setup accuracy with traditional skin marks. In addition, SGRT significantly reduced the time from initial patient positioning to treatment, suggesting that SGRT can be effectively used in hypofractionated whole breast irradiation without the need for skin marks, potentially enhancing patient comfort and convenience.