Abstract Purpose/Objective: Intraoperative radiation therapy (IORT) is a form of accelerated partial breast irradiation (APBI) delivered at the time of lumpectomy for early-stage breast cancer. Upfront selection of patients based on favorable preoperative characteristics is important to achieve good outcomes. Here we present our single-institution experience in the management of invasive breast cancer with IORT. We focused on the classification of patient suitability for IORT by the American Society for Therapeutic Radiation Oncology (ASTRO) APBI consensus guidelines using preoperative and postoperative clinicopathologic factors, as well as treatment outcomes and recurrences. Materials/Methods: We reviewed our institutional prospective registry database (AAAJ8512) to identify patients with biopsy-proven invasive breast cancer treated with breast IORT between 9/2013 and 4/2020 using the Zeiss Intrabeam™. Patients received a single dose of 20Gy delivered to the lumpectomy cavity surface at the time of planned surgery. We excluded patients from analysis with prior radiation to the breast, or triple negative disease at initial diagnosis. We reviewed preoperative and postoperative clinicopathologic factors to determine each patient’s ASTRO APBI suitability (suitable, cautionary or unsuitable) based on the 2017 consensus guidelines. Results: 237 patients were treated with IORT for early stage breast cancer. Median age was 67 years (range 44-94 years). Median extent of disease by conventional imaging was 1.0 cm (range 0 - 3.0cm). 51/103 (49.5%) patients with heterogeneously or extremely dense breasts underwent a MRI preoperatively. Based on preoperative clinicopathologic characteristics, 191 (80.6%) patients were suitable according ASTRO APBI guidelines, 46 (19.4%) cautionary and no patients were unsuitable. APBI group suitability changed in 95 (40.1%) patients based on final pathology from the time of lumpectomy, summarized in Table 1. 17 (7.2%) patients underwent re-excision for close or positive margins. 39 (16.5%) patients received additional adjuvant whole breast radiotherapy including 10/18 (56%) of unsuitable patients. Of 212 (89.5%) patients who initiated hormone therapy (HT), 191 (80.6%) were compliant at last follow up. Median follow-up for all patients was 38.2 months (0.4 - 74.5). Five (2.1%) patients experienced ipsilateral breast tumor recurrence, 1 (0.4%) patient experienced new contralateral breast cancer, and 2 (1.6%) patients experienced distant recurrence with the median time to event of 27.8 months (range 6.3-50.4). Of the 5 patients with ipsilateral breast tumor recurrence, 2 (0.8%) were true local recurrences <2cm from the initial lumpectomy bed with the same histology as initial tumor, both cases were cautionary risk and one declined HT, 3 (1.3%) were new breast primaries occurring >2cm from lumpectomy bed with a different histology. Conclusion: Breast IORT is an attractive cost-effective option for women with early stage breast cancer, and our 3-year true local recurrence rate is 0.8%. Optimal patient selection is key based on preoperative characteristics. Patients who become unsuitable or cautionary for APBI based on final pathology should be considered for additional adjuvant therapy. Table 1ReasonASTRO APBI Pre-Op Suitability#SizeER (-)AgeT2ILCSuitable191Cautionary46114101122Unsuitable0ASTRO APBI Post-Op Suitability Change#SizeClose MarginsPositive MarginsLVIMultifocalILCEICSuitable to Cautionary7792023211124Suitable to Unsuitable12111Cautionary to Unsuitable624Abbreviations: ER = Estrogen Receptor; ILC = Invasive Lobular Carcinoma; LVI = Lymphovascular Invasion; EIC = Extensive Intraductal Component Citation Format: Andrea M Brown, Christine Chin, Eileen Connolly, Roshni Rao, Bret Taback, Lisa Wiechmann. Preoperative selection of patients with early-stage invasive breast cancer for intraoperative radiation therapy (IORT): A single-institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-19.