To determine potential improvement of patient setup accuracy and efficiency using Surface Guided Radiation Therapy (SGRT) instead of traditional three-point markers for breast irradiation. The current standard for patient positioning at isocenter uses at least three markers, placed directly on the skin (e.g., tattoos or other semi-permanent methods). Multiple sets of marks are often required as significant shifts are determined during the treatment planning process and/or throughout treatment to match image guidance. Anecdotally, patients often complain about the inconvenience and cosmetic disadvantages of maintaining skin marks. Contrastingly, SGRT uses visual (non-ionizing), real-time monitoring of the patient’s external surface contour and quantitatively compares to a calculated or acquired reference image. If proven at least as accurate and efficient as the traditional setup technique, SGRT potentially allows for the abandonment of physical marking systems. Data was collected for over 250 breast treatments involving 17 patients over a 90 day period. For each patient, half the total fractions were setup using the SGRT method, while the remaining fractions were setup using the three-point marker method. Total setup time was also tracked during each verification procedure, which is typically much longer in duration than a normal treatment fraction. For each patient, the same therapist(s) performed all setups to reduce variability. Data recorded for each fraction included total time in treatment room, source-to-surface distance (SSD; as compared to the expected value from the treatment planning system), and the magnitude of couch shifts based on weekly image guidance (as determined by a physician). The average magnitude of time spent setting up and treating breast patients via the three-point marker technique was 5.48 ± 1.52 minutes. Contrastingly, using SGRT, the respective times were consistently lower, at an average of 4.72 ± 0.87 minutes. The average shift magnitudes subsequent to setup and based on image guidance was 0.71 ± 0.29 cm for the marker setups, but reduced to 0.47 ± 0.31 cm for SGRT setups. The average difference in SSD (treatment plan vs. final treatment position) was 0.30 ± 0.14 cm using the three-point setup, and 0.27 ± 0.12 cm for SGRT setup. Statistically significant differences in efficiency and accuracy were similarly recorded during initial setup (i.e., verification) appointments. SGRT setup for breast patients was observed to be more accurate and efficient than the marker-based technique. Fully utilizing SGRT allows for the implementation of a completely markless system of simulation and treatment, thereby simultaneously improving patient satisfaction, throughput, and setup accuracy. This study demonstrates potential similar improvements if SGRT is applied to the entire spectrum of treatment sites.