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ABSTRACT: To report the feasibility, toxicity, cosmesis, and efficacy of using intensity-modulated radiation therapy (IMRT) with respiratory gating to deliver accelerated partial breast irradiation (APBI) in selected Stage I/II breast cancer after breast-conserving surgery. Eligible patients with node-negative Stage I/II breast cancer were prospectively enrolled in an institutional review board approved protocol to receive APBI using IMRT after breast-conserving surgery. The target volume was treated at 3.8 Gy/fraction twice daily for 5 days, to a total dose of 38 Gy. Thirty-six patients were enrolled for a median follow-up time of 44.8 months. The median tumor size was 0.98 cm (range, 0.08-3 cm). The median clinical target volume (CTV) treated was 71.4 cc (range, 19-231 cc), with the mean dose to the CTV being 38.96 Gy. Acute toxicities included Grade 1 erythema in 44% of patients and Grade 2 in 6%, Grade 1 hyperpigmentation in 31% of patients and Grade 2 in 3%, and Grade 1 breast/chest wall tenderness in 14% of patients. No Grade 3/4 acute toxicities were observed. Grade 1 and 2 late toxicities as edema, fibrosis, and residual hyperpigmentation occurred in 14% and 11% of patients, respectively; Grade 3 telangiectasis was observed in 3% of patients. The overall cosmetic outcome was considered "excellent" or "good" by 94% of patients and 97% when rated by the physician, respectively. The local control rate was 97%; 1 patient died of a non-cancer-related cause. APBI can be safely and effectively administered using IMRT. In retrospective analysis, IMRT enabled the achievement of normal tissue dose constraints as outlined by Radiation Therapy Oncology Group 04-13/NSABP B-13 while providing excellent conformality for the CTV. Local control and cosmesis have remained excellent at current follow-up, with acceptable rates of acute/late toxicities. Our data suggest that cosmesis is dependent on target volume size. Further prospective multi-institutional trials should be performed to evaluate IMRT to deliver APBI.