Purpose The aim of the current study was to compare toxicity, cosmesis, and local control between the once daily and the twice daily fractionation schemes for external beam accelerated partial breast irradiation. Methods and Materials From December 2012 to June 2018, we enrolled 113 patients with ductal carcinoma in situ or invasive breast cancer, node negative disease, and tumors less than 3 cm in size to receive accelerated partial breast irradiation (APBI) to a total dose of 38.5 Gy over 10 fractions given either once (oAPBI) or twice daily (tAPBI). Sixty patients were included in the tAPBI arm and 53 patients were included in the oAPBI arm. Results Median follow-up was 74 months (range, 24-105). The median pain score during treatment was 3 out of 10 in the oAPBI and 5 in the tAPBI (P = .001). No differences were observed in GIII early skin toxicity (P = .4) or GI early pulmonary toxicity (P = 1.0) between the 2 treatment arms. GIII late skin toxicity developed in 3.8% and 11.7% of patients in the oAPBI and tAPBI arms, respectively (P = .001). GIII subcutaneous fibrosis developed in 1.9% and 8.3% of patients in the oAPBI and tAPBI, respectively (P = .001). The rate of patients with adverse cosmesis (poor/fair) was 7.5% at 12 months and at 24 months in the oAPBI arm compared with 21.7% and 26.7% in the tAPBI arm (P = .03 and .008, respectively). Conclusions oAPBI is a safe, well-tolerated schedule with more favorable outcomes than the tAPBI schedule with regards to late toxicity and cosmesis.