To assess for the first time the safety and feasibility of combining photon-intraoperative radiotherapy (ph-IORT) with hypofractionated whole breast irradiation (h-WBI) in patients referred to primary systemic therapy (PST). From March 2019 to December 2020, patients referred for breast conservative surgery (BCS) after PST in our institution were prospectively included in the present trial. PST was prescribed to all patients according the ESMO-SEOM guidelines. Once the PST was completed, BCS was discussed in the multidisciplinary tumor board (MTB). 20Gy were prescribed to the surface of the applicator of an Intrabeam®photon-IORT during BCS. h-WBI (40.5Gy/2.67Gy/15frx) was planned to be administered 3-5w after BCS. All patients were treated with hWBI VMAT-Rapid-Arc&Daily Exac-Trac-IGRT. The primary end points of the study were feasibility and safety (grade 3 toxicity rate CTCAE.5.0-scale) of the proposed treatment protocol. The secondary end points included cosmetic results (Harvard Scale), local relapse rate and overall survival. Thirty-five patients were included in the trial. The median age was 54years. Tumor size was > 2cm in all cases. Eighteen patients were N + (51.4%). There was no disease progression during PST. All patients received the planned 20Gy-ph-IORT boost at the time of BCS and the proposed h-WBI. 31/35 (88,6%) patients started h-WBI within the predefined time period (3-5w after BCS). No patient showed ≥ G3 acute toxicity 3months after the end of h-WBI. No ≥ G3 late toxicity was observed at 12months of follow-up and thereafter. Cosmetic results were scored excellent/good in 26 patients (74.2%). After a median follow-up of 52months, a TNBC patient locally relapsed at 13months of follow-up. We demonstrated for the first time that ph-IORT + hWBI is feasible and safe in patients referred to BCS after PST.