Abstract: Objective To compare the efficacy and influence factors between everolimus in combination with endocrine therapy and endocrine therapy alone in HR positive advanced breast cancer patients after multi-line treatments. Methods Ninety-six heavily pretreated patients with HR positive advanced breast cancer admitted to Affiliated Hospital of Academy of Military Medical Science from August 2010 to November 2013 were enrolled in this study. Patients were divided into two groups:one treated with everolimus combined with endocrine therapy (n=48), the other with endocrine therapy alone (n=48). The efficacy and adverse events of two regimes were compared and investigated and the influence factors were analyzed. Results Baseline disease characteristics of patients in two groups were well balanced. Clinical benefit rate (CBR) in everolimus plus endocrine therapy and endocrine therapy alone were 22.9% and 8.3% (P=0.049). Median progression free survival (PFS) were 4.0 months (95% CI:2.9-5.1) and 2.0 months (95% CI:1.8-2.2) in the two groups respectively, which was of statistically significant difference (P=0.001). The subgroup analysis showed that in patients ≥ 50 years old, ER positive, PR positive, Her-2 negative, visceral metastasis, bone metastasis, soft tissue metastasis, brain metastasis, recurrence or progression after treated less than 5 regimes, or previously sensitive to endocrine therapy, PFS of everolimus plus endocrine therapy was longer than that of endocrine therapy alone. Both the Cox single factor and multivariate regression analysis showed that previous sensitivity to endocrine therapy was an independent correlative factor to PFS. The major toxicities related to everolimus included 1-2 grade stomatitis, interstitial pneumonia and so on. Conclusion Combination of everolimus and endocrine therapy is effective in patients with HR positive advanced breast cancer after multi-line treatment, and it also can prolong the progression caused by endocrine resistance.