Background Breast-conserving therapy (BCT) with WBI is an accepted option in the treatment of most patients with stage 1 or 2 breast cancer, but not all eligible patients utilize it. This may be because of age, length of time required for WBI treatment and availability of this method, and burden of care. There is a large body of mature phase I and II data, and some preliminary phase III data, that relate to the replacement of WBI after lumpectomy with PBI delivered in 4–5 days and restricted to the region of the tumor bed. Can an acceptable outcome be achieved with radiation therapy (RT) delivered only to the region of the tumor? Trial design: For the administration of WBI, we are using standard techniques delivered over 5–7 weeks as outlined in the B-39/0413 protocol. For the adminsitration of PBI, we are using high-dose-rate multi-catheter brachytherapy, high-dose-rate single-entry intracavitary brachytherapy (MammoSite®, MammoSite® ML, Contura™ MLB, and SAVI®), and 3D conformal external beam RT. PBI is given twice a day, at least 6 hours apart, on 5 treatment days over a period of 5–10 days. The technique selected depends on technical considerations, radiation oncology facility technique credentialing, and patient preference. Before random assignment, patients must have a planning CT. Those randomized to WBI receive chemotherapy, if applicable, before their RT. Those randomized to PBI receive RT before chemotherapy, if applicable. All treatment sites must pass a rigorous QA and QC process for PBI before and during the duration of the study. We are using a QOL program to assess cosmesis, fatigue, symptoms, and perceived convenience of care. Eligibility criteria: Patients must have stage 0 or stage 1 or 2 IBC with no evidence of metastatic disease. Tumor size must be 3 cm or less. Women must have undergone a lumpectomy with the margins of the resected specimen histologically free of cancer, including DCIS. Patients must have no more than 3 positive axillary nodes. Accrual is open to all premenopausal women and to postmenopausal women who have IBC that is ER/PR negative or node positive. Patients are stratified according to disease stage, menopausal status, hormone receptor status, and intention to receive chemotherapy. Following stratification, patients are randomly assigned to receive WBI or PBI. Specific aims: The primary endpoint is the comparison of those receiving PBI and WBI for the diagnosis of in-breast tumor recurrence (IBTR). The study will also compare women receiving PBI and WBI for overall survival, recurrence-free survival, and distant disease-free survival. QOL aims are related to cosmesis, fatigue, treatment-related symptoms, and perceived convenience of care. Statistical analysis and accrual: PBI and WBI will be declared equivalent if the estimated relative risk of IBTR falls between 0.86 and 1.17. Analysis will occur after 175 IBTRs are diagnosed. At the end of May 2011, accrual was 3962 of 4300 patients. Supported by PHS grants NCI-U10-CA-69651, NCI-U10-CA-12027, and NCI P30-CA-14599 from the US NCI. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-06-02.