B-cell lymphoma-2 (Bcl-2) is one of the most important anti-apoptotic genes. Although Bcl-2 promotes tumor cell survival in vitro, previous studies have shown conflicting results regarding the association between Bcl-2 and breast cancer survival. The aim of this study was to assess the prognostic significance of Bcl-2 according to the molecular tumor subtype in primary invasive breast cancer patients. The relationship between immunohistochemical Bcl-2 expression and overall survival was analyzed in 2399 primary invasive breast cancer patients treated by curative surgery. Patients were classified into four subtypes based on hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status: HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. A total of 1304 patients (54.4 %) had Bcl-2 positive (+) tumors by immunohistochemistry. Bcl-2 (+) tumors were significantly associated with a younger age (<50 years), early stage, lower grade, positive expression of HR, and negative expression of HER2. In the HR+/HER2- group, patients with Bcl-2 (+) tumors showed a significantly better prognosis (p < 0.001). In contrast, there was no significant prognostic effect of Bcl-2 expression in other subtypes. In multivariate analysis, Bcl-2 positivity remained an independent, favorable prognostic factor in the HR+/HER2- subtype (hazard ratio, 0.609; 95 % confidence interval, 0.424-0.874; p < 0.007). The prognostic significance of Bcl-2 expression differed according to the molecular subtype of breast cancer. The expression of Bcl-2 was an independent, favorable prognostic factor in breast cancer patients with the HR+/HER2- subtype.