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METHODS This retrospective study evaluated patients who received three-fraction accelerated partial breast irradiation (APBI) via brachytherapy for breast cancer between January 2016 and April 2020. Inclusion criteria included age ≥18 years and early-stage unilateral breast cancer with negative lymph nodes. We evaluated acute toxicity (<6 weeks), late toxicity (≥6 weeks), and cosmetic outcomes. Frequencies of each variable were calculated. Cancer-specific outcomes were determined via the Kaplan-Meier method. RESULTS Thirty consecutive patients received three-fraction APBI of 2,250 cGy over 2 d. All cancers were stage T2 or less. Median time to last follow-up was 22 months. Local recurrence-free survival was 95.8% at 22 months. Seventeen (56.7%) patients reported an acute toxicity event. All were grade 1 except one patient with grade 2 (fatigue). No patient experienced ≥ grade 3 acute toxicity. One (3.3%) patient reported grade 3 late toxicity (tissue fibrosis). No patients had breast edema, fat necrosis, or non-healing wounds. There were no ≥ grade 3 cosmetic events. DISCUSSION Three-fraction APBI via brachytherapy was successful in preventing disease recurrence and death in this study, with still limited follow-up. Although acute and late toxicities or adverse cosmetic outcomes were seen, very few were grade 2 or higher and compare favorably to those reported in prior 10-fraction APBI studies. CONCLUSIONS This study provides early single institutional evidence that three-fraction APBI may become a feasible treatment alternative.