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Purpose: To compare the efficacy and safety profile of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and fulvestrant versus fulvestrant alone in previously treated patients with advanced hormone-receptor positive breast cancer. Methods: Phase III randomized clinical trials (RCTs) were retrieved from a systematic review of electronic databases. A random-effect model was employed to determine the pooled hazard ratio (HR) for Progression-Free Survival (PFS) and Overall Survival (OS) using the inverse-variance method. The Mantel Haenszel method was used to calculate the pooled odds ratio (OR) for treatment-related side effects. Heterogeneity was measured using the tau-squared and I2 statistics. Results: Three phase III RCTs (n = 1916) were included in the systematic review. Use of abemaciclib, palbociclib, or ribociclib in combination with fulvestrant was significantly associated with longer PFS compared to use of fulvestrant alone (HR: 0.53; 95%CI: 0.47–0.60; p<0.00001), with no significant heterogeneity found among trials. Similarly, OS was significantly longer for patients who received combination therapy in comparison with those allocated to receive fulvestrant alone (HR: 0.77; 95%CI: 0.67–0.89; p<0.0004). The overall odds ratio of serious adverse events (AE) was not significantly increased with the use of the combination therapy (OR: 1.51; 95%CI: 0.74–3.08), with significant heterogeneity found among trials (tau2=0.34; I2=86%; p = 0.0006). Conclusion: The addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to fulvestrant significantly improved PFS and OS in comparison with fulvestrant alone in patients previously treated with endocrine therapy for advanced breast cancer. No significant heterogeneity was found among CDK 4/6 inhibitors.