Background: A planned interim analysis of an institutional Phase II trial of once-weekly radiotherapy for patients undergoing breast-conserving surgery (BCS). Methods: Patients who underwent BCS for AJCC Stage 0, I or II breast cancer with negative surgical margins were eligible to receive whole-breast radiotherapy to a dose of 30Gy in 5 weekly fractions of 6 Gy with or without an additional boost. There were no restrictions on age, breast size or the use of cytotoxic chemotherapy for otherwise eligible patients. Patients were evaluated at baseline, 6 and 12 months with digital photography, physician assessment of cosmesis (Harvard Scale) and self-assessment (BCTOS). Results: Between January 2011 and January 2013, 82 eligible patients underwent WHBI immediately following BCS (82.7%) or at the conclusion of adjuvant cytotoxic chemotherapy (17.3%). The median age was 60 years (range: 30-80y) and the median followup was 33.1 months and all patients had at least 1 year followup. The rate of Excellent/Good vs. Fair/Poor cosmesis at 12 months was 77.3% vs. 22.7%. The rate of significant cosmetic change from baseline was 14.7%. The only factor predictive of significant cosmetic change was smoking status (OR: 6.94; p = 0.016). The median BCTOS score increased only slightly from baseline (31) to one year (32), with patient-reported breast size differences worsening but complaints of pain improving over the study period. Conclusions: Cosmetic outcome after WHBI compares well with reports of daily hypofractionated whole-breast irradiation. Further follow-up with continued accrual is needed to assess cosmetic stability and disease-specific outcomes. Clinical trial information: NCT01278212.