ObjectivePatients with triple-negative (TN) or human epidermal growth factor 2 (HER2)-enriched ipsilateral breast cancer recurrence (IBCR) seem to be excluded from a second breast-conserving surgery (BCS) under the assumption that salvage mastectomy would provide better oncological outcomes. The objective of this study was to describe the clinical features of these patients, to compare the two surgical alternatives (salvage mastectomy versus second BCS) in terms of oncological results, and to identify independent factors influencing prognosis and surgical treatment. Materials and MethodsWe retrospectively reviewed all the consecutive patients with histologically confirmed TN or HER2-enriched IBCR. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. ResultsEighty-five patients were affected by TN or HER2-enriched IBCR. The majority of patients (72.9%) were treated with salvage mastectomy. There was no significant difference in terms of DFS between patients receiving a second BCS or mastectomy (p = 0.596). However, patients undergoing a second BCS had significantly better DDFS, OS and BCSS compared to mastectomy (p = 0.009; p = 0.002; p = 0.001, respectively). Tumor dimension <16 mm was found to significantly increase the probability of receiving a second BCS and positively affects recurrence and survival outcomes. Salvage mastectomy represents an independent poor prognostic factor for OS and BCSS. ConclusionSalvage mastectomy is not always necessary and it does not seem to increase survival compared to a second BCS. In patients with small aggressive subtypes of IBCR, a second conservative approach can still be evaluated and offered, presenting acceptable loco-regional control and survival.