Purpose: The predictive significance of the Naples prognostic score (NPS) in HER2-positive breast cancer is unclear. Hence we sought to evaluate the relationship between NPS and the clinical outcomes in HER2-positive breast cancer patients. Methods: This study retrospectively collected and analyzed data from 173 HER2-positive breast cancer patients between August 2004 and February 2014. The Cox regression model was applied in univariate and multivariate statistical analysis. Results: In multivariate analysis, increased NPS score correlated significantly with poor overall survival (p = 0.001) and disease-free survival (p < 0.001). Conclusion: Our findings may point to NPS being a novel and reliable prognostic score system with favorable predictive ability for HER2-positive breast cancer patients.Breast cancer is one of the most frequent cancers in females and the second leading cause of death among women worldwide. HER2-positive breast cancer has the characteristics of rapid growth, high risk of relapse and cancer migration and spreading. The predictive significance of the Naples prognostic score (NPS) in HER2-positive breast cancer is unknown. We hypothesized that NPS may improve prediction of outcomes in HER2-positive patients. A statistical analysis was conducted. Our results revealed that NPS was an independent predictive factor of overall survival and disease-free survival in patients with HER2-positive breast cancer.