Objectives: Trastuzumab, a humanized monoclonal antibody that binds human epidermal growth factor receptor 2 (HER2), dramatically improves the clinical outcomes of HER2-positive breast cancer. Emerging evidence implied that the clinical behavior and sensitivity to targeted agents in HER2-positive breast cancer differed by hormone receptor (HR) status. The objective of this study was to determine the effect of the HR status on survival benefit of HER2-positive metastatic breast cancer when treated with anti-HER2-targeted therapy in People's Republic of China. Methods: Metastatic breast cancer patients with HER2-positive diseases across six cancer centers in People's Republic of China were retrospectively analyzed in our study. Patients were classified into four groups according to HR/HER2 status and trastuzumab treatment: HER2+/HR+ patients with first-line trastuzumab treatment, HER2+/HR+ patients with no trastuzumab treatment, HER2+/HR-patients with first-line trastuzumab treatment, and HER2+/HR-patients with no trastuzumab treatment. Kaplan-Meier analysis, log-rank test, and multivariate analysis were performed during analysis. Results: A total of 295 patients were included in the final analysis. The median overall survival was 30 months (95% confidence interval: 27.521-32.479). Among patients with HER2+/HR-disease, significant survival benefit was observed when treated with trastuzumab (30 vs 21 months, P=0.000). However, in patients with HER2+/HR+ disease, trastuzumab administration had a survival improvement trend but no significant statistical differences (36 vs 30 months, P=0.258). In the multivariate analysis, HR status was an independent predictor of overall survival and trastuzumab treatment had significantly decreased risk of death in HER2+/HR-patients (hazard ratio = 0.330). Conclusion: HR status is an independent predictor of overall survival in HER2-positive metastatic breast cancer patients and patients with HER2+/HR-subtype might be associated with more survival benefits when treated with trastuzumab-based regimens.