INTRODUCTION: Conventional whole breast radiotherapy reduces in-breast tumor recurrence after lumpectomy for breast cancer.Accelerated, partial breast irradiation (APBI) treats the lumpectomy cavity margins alone and delivers the equivalent of whole breast treatment in only 1 to 5 days.Single fraction intra-operative radiotherapy (IORT) is the most accelerated form of APBI.There is limited U.S.experience with IORT.The purpose of this study was to determine if single fraction IORT after lumpectomy is feasible and safe.METHODS: Women age≥40 with biopsy proven, primary invasive ductal carcinoma (IDC), mixed IDC/ductal carcinoma in situ (DCIS), or pure DCIS were considered in this IRB approved study.Magnetic resonance imaging (MRI) was performed for local staging and to exclude satellite lesions: if found, these were biopsied preoperatively.Women with single lesions that appeared less than 2.5 cm were offered IORT.Lumpectomy was guided by palpation or image guidance (xray, ultrasound, and/or MRI).Sentinel node biopsy was performed as indicated.IORT was cancelled if margins or nodal status were uncertain.IORT was delivered with a Philips orthovoltage x-ray machine via a collimator with a 17 Gy surface dose.Final path requirements included: unifocal lesion, T ≥ 2.5 cm, margins ≥2 mm.Exclusion criteria were extensive in-situ component and sentinel node involvement.Close or positive margins required re-excision.If residual disease was absent, no further radiotherapy was given.RESULTS: 46 women received IORT.4 required re-excision, of whom 2 had no residual disease.5 of 46 did not meet study criteria: of these, 4 refused additional radiotherapy.9 patients were excluded intraoperatively.Major complications included: 1 infected hematoma requiring incision and drainage; 1 clinical fat necrosis requiting excision; 1 abscess requiting incision and drainage, with closure over a drain.6 patients required minor scar revision due to extensive skin retraction early in our study.At 42 months median followup, there is 1 death from metastatic colon cancer.There were two in-breast tumor recurrences requiring mastectomies, 1 each in the protocol and "off" protocol groups, respectively.CONCLUSION: Single fraction IORT following lumpectomy is feasible, safe, and warrants further evaluation in the U.S.