Simple SummaryDespite its crucial impact on treatment accuracy and therefore patient safety, image-guided radiation therapy (IGRT) during adjuvant breast radiotherapy widely lacks standardized recommendations and guidelines. A wide variation of different IGRT methods and schedules is used in radiotherapy centers over the world, yet reliable evidence remains sparse for most of these approaches. In this study, we took a closer look at a common approach, by which IGRT frequency is altered based on the magnitude of setup errors in the beginning of the radiotherapy treatment.The current study aims to assess the suitability of setup errors during the first three treatment fractions to determine cone-beam computed tomography (CBCT) frequency in adjuvant breast radiotherapy. For this, 45 breast cancer patients receiving non-hypofractionated radiotherapy after lumpectomy, including a simultaneous integrated boost (SIB) to the tumor bed and daily CBCT imaging, were retrospectively selected. In a first step, mean and maximum setup errors on treatment days 1–3 were correlated with the mean setup errors during subsequent treatment days. In a second step, dose distribution was estimated using a dose accumulation workflow based on deformable image registration, and setup errors on treatment days 1–3 were correlated with dose deviations in the clinical target volumes (CTV) and organs at risk (OAR). No significant correlation was found between mean and maximum setup errors on treatment days 1–3 and mean setup errors during subsequent treatment days. In addition, mean and maximum setup errors on treatment days 1–3 correlated poorly with dose coverage of the CTVs and dose to the OARs. Thus, CBCT frequency in adjuvant breast radiotherapy should not be determined solely based on the magnitude of setup errors during the first three treatment fractions.