Abstract Hypofractionated whole-breast irradiation (HF-WBI), a radiotherapy with a larger dose per fraction and a shorter schedule for early-stage breast cancer patients post breast-conserving surgery, shows equivalent safety and efficacy compared to conventionally fractionated whole-breast irradiation (CF-WBI) regarding local recurrence and disease-free survival. While several countries have set HF-WBI as the preferred standard of care for these patients, its uptake in the U.S. has lagged behind expectations. We used the Health Care Cost Institute (HCCI) database 2008-2017, covering a third of the U.S. employer-sponsored insurance population, to identify early-stage breast cancer patients. Patients were clustered at different geographic levels (Census region, state, core-based statistical area (CBSA), hospital referral region of Dartmouth Atlas, and zip code) and the radiation oncologist level. These two levels are cross-nested. We used a Bayesian cross-classified multilevel logistic model to simultaneously model the geographic units variability and physician-level variability in HF-WBI use across the U.S. Variation metrics included intracluster correlation coefficient (ICC) and median odds ratios (MOR). ICC with a value of 0 is equivalent to MOR of 1, indicating identical outcomes across all levels. After accounting for these variations in the cross-classified multilevel model framework, we evaluated the association between HF-WBI use and clinical and demographic factors.Our study included 79,747 women (74.0%) who underwent CF-WBI and 27,999 (26.0%) who received HF-WBI. HF-WBI adoption increased over time (2008-2017). Variability across radiation oncologists (ICC = 0.272, MOR = 2.88) was notably larger than geographic areas variability. Variability across CBSA (ICC = 0.097, MOR = 1.76) was the strongest among all the geographic levels. The variation in HF-WBI use was mainly attributed to physician-level variability (ICC=0.222, MOR=2.59) based on the cross-classified multilevel model. No substantial differences were found between young (aged 64 or younger with commercial health plans) and older patients (aged 65 or older with Medicare Advantage plans) in terms of both geographic and physician-level variations. After accounting for variability in radiation oncologists and CBSAs, older age, non-reception of chemotherapy, and several community-level factors, including longer distance from home to facility and higher community education level, were associated with a higher likelihood of HF-WBI use. These results may lend insights into potential facilitators/barriers to HF-WBI uptake. Future studies can further investigate the impact of the 2018 American Society for Radiation Oncology (ASTRO) guideline and the Covid-19 pandemic on HF-WBI use, which would illuminate potential improvements of healthcare practices. Citation Format: Yijia Sun, Loren Saulsberry, Chuanhong Liao, Donald Hedeker, Dezheng Huo. Geographic and physician-level variation in the use of hypofractionated radiotherapy for breast cancer in the U.S.: A cross-classified multilevel analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4846.