This prospective Phase II single-arm study gathered data on the use of intensity-modulated radiotherapy (IMRT) to deliver accelerated partial breast irradiation (APBI). Four-year efficacy, cosmesis, and toxicity results are presented. Between February 2004 and September 2007, 136 consecutive patients with Stage 0/I breast cancer and negative margins ≥0.2 cm were treated on protocol. Patients received 38.5 Gy in 10 equal fractions delivered twice daily. Breast pain and cosmesis were rated by patient, and cosmesis was additionally evaluated by physician per Radiation Therapy Oncology Group (RTOG) criteria. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) was used to grade toxicities. 136 patients (140 breasts) with median follow-up of 53.1 months (range, 8.9-83.2) were evaluated. Population characteristics included median age of 61.9 years and Tis (13.6 %), T1a (18.6 %), T1b (36.4 %), and T1c (31.4 %). Kaplan-Meier estimates at 4 years: ipsilateral breast tumor recurrence 0.7 %; contralateral breast failure 0 %; distant failure 0.9 %; overall survival 96.8 %; and cancer-specific survival 100 %. At last follow-up, patients and physicians rated cosmesis as excellent/good in 88.2 and 90.5 %, respectively; patients rated breast pain as none/mild in 97.0 %. Other observations included edema (1.4 %), telangiectasia (3.6 %), five cases of grade 1 radiation recall (3.6 %), and two cases of rib fractures (1.4 %). This analysis represents the largest cohort and longest follow-up of APBI utilizing IMRT reported to date. Four-year results continue to demonstrate excellent local control, survival, cosmetic results, and toxicity profile.