Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumour bed boost after breast conserving surgery is well established for women with early breast cancer. A previous study from our group shows a beneficial effect of TARGIT-IORT on overall survival (OS) but not disease-free survival (DFS) after neoadjuvant chemotherapy compared to an external boost suggesting a potential non-inferiority of TARGIT-IORT. In this study, we present results regarding the high-risk subset of patients (i.e. with triple negative (TN) and HER2 positive tumours) from this cohort. In this non-randomized cohort study involving patients with HER2 positive (n= 28) and triple negative (n=42) tumours after NACT we compared outcomes of 40 patients with tumour bed boost applied with TARGIT IORT during lumpectomy versus 30 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Rates of DFS and OS were compared. Median follow up was 49 months. In comparison of TARGIT-IORT vs. EBRT 5-year Kaplan- Meier estimates of OS showed no significant difference among patients with HER2 positive tumours (100% vs. 91.7%, log rank p = 0.22). The same was seen for DFS (83.3% vs. 77.0%, log rank p=0.38). The results for TN cases were similar (OS : 87.5% vs. 74.1%, log rank p=0.488; DFS 87.5% vs. 60%, log rank p=0.22). Although survival estimates trended towards favouring TARGIT-IORT, no significant differences could be observed and the significantly positive result for OS favoring TARGIT-IORT in the whole cohort of 116 patients could not be reproduced in this subset analysis of patients with TN and HER2 positive tumours. This may be contributable to the limited number of patients but may also indicate that effects seen in the whole cohort were mainly driven by ER and/or PR positive and HER2 negative tumours. Most importantly, non-inferiority of TARGIT-IORT as an intraoperative boost could be reproduced in these high-risk patients.