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Objective: The aim of this retrospective study was to assess the risk factors for developing ipsilateral breast tumor reappearance (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (from June 1994 to December 2006). Clinicopathological features, follow-up, and survival at 15 years were considered for statistical analysis. Results: Significant associations of increased risk for IBTR were verified with metastatic axillary lymph nodes (HR 1.37 [1.15–1.62], p = 0.0004), high tumor grade G2 (HR 1.35 [1.05–1.74], p = 0.02) and G3 (HR 1.35 [1.01–1.79], p = 0.04), luminal B (HR 1.51 [1.25–1.82], p < 0.0001), and HER2-positive (HR1.66 [1.14–2.41], p = 0.008) and triple-negative subtype (HR 1.54 [1.07–2.21], p = 0.02). Older age (HR 1.44 [1.08–1.91], p = 0.01) and positive family history (HR 1.85 [1.47–2.32], p < 0.0001) were risk factors for contralateral BC. Significant protective factors for IBTR were hormonotherapy (HR 0.71 [0.59–0.85], p = 0.0003), chemotherapy (HR 0.72 [0.60–0.87], p = 0.001), and radiotherapy (HR 0.73 [0.61–0.87], p = 0.0005). Hormonotherapy was also confirmed as a protective factor for contralateral second BC (HR 0.43 [0.30–0.60], p < 0.0001). Conclusions: We classified factors for IBTR and contralateral BC in high- and low-risk groups. In the high-risk group, breast surgery still remains more important than in the low-risk group, which seems to benefit more from adjuvant treatments. [ABSTRACT FROM AUTHOR]