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Purpose: We investigate the feasibility of surface guided radiation therapy (SGRT) for accelerated partial breast irradiation (APBI) by comparing it with in‐room, fan beam kV computed tomography on rails (CTOR) imaging of the targeted region. The uniqueness of our study is that all patients have multiple daily CTOR scans to compare corresponding SGRT AlignRT (VisionRT, United Kingdom) images to. Methods/materials: Twelve patients receiving APBI were enrolled in this study. Before each treatment fraction, after patients were setup on tattoos, SGRT was performed using AlignRT, and then target matching was performance using CTOR. The average and maximum difference in shifts between SGRT and CTOR were calculated and analyzed for each patient, so as the correlation between surgical cavity size and shift difference. Results: Our study showed that SGRT agreed well with CTOR for patients with small surgical cavity volume changes (<10%). There were nine patients who had a ≥5 mm maximum shift difference between SGRT and CTOR along any direction, and in two patients the difference was more than 10 mm (one patient with surgical cavity change 44.3% and one patient with 27 cc cavity volume decrease). All patients, except one, had a mean shift difference < 5 mm along any direction. Conclusion: For the patients studied here, SGRT appears to be a reasonable and potentially valuable image guidance approach for APBI for patients who experience small changes in surgical cavity volume (<10%) between CT simulation and treatment. However, there is potential for larger alignment errors (up to 11 mm) when using SGRT for patients who experience larger surgical cavity changes. [ABSTRACT FROM AUTHOR]