Objective: This study investigated the effectiveness and safety of everolimus plus endocrine therapy in patients with hormone receptor- positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) after failed cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy in a real-world clinical setting. Material and Methods: This was a single-center retrospective cohort study. Patients with HR+/HER2- MBC who underwent everolimus plus endocrine therapy after prior progression with combination of a CDK4/6 inhibitor and a hormonal therapy were included. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan- Meier method, and parameters associated with PFS were assessed by Cox regression analysis. Results: A total of 44 patients were included. The median PFS was 4.1 months [95% confidence interval (CI), 2.8-5.4] and the median OS was 16 months (95% CI, 8.8-23.2). Liver metastasis [hazard ratio (HR), 2.28; 95% CI, 1.09-4.78; p=0.029] and pleural or peritoneal metastases (HR, 3.23; 95% CI, 1.46-7.14; p=0.004) were associated with poor PFS. Multivariate Cox regression analysis after covariate adjustment for age and histology revealed that liver (HR, 2.21; 95% CI, 1.04- 4.69; p=0.038) and pleural or peritoneal metastases (HR, 3.01; 95% CI, 1.35-6.70; p=0.007) were significantly associated with increased risk of PFS events. Conclusion: Everolimus plus endocrine therapy has a moderate effect on PFS in patients with MBC who had previously received a CDK4/6 inhibitor and hormonal agent combination therapy. The effect is more pronounced in patients without liver or pleural/peritoneal metastases.