Background: Molecular heterogeneity in breast cancer has led to increasing attention in the role of cell cycle signaling especially the cyclins and their associated proteins, cycle-dependent kinases (CDK), in carcinogenesis and treatment resistance in hormone receptor-positive metastatic breast cancer. Many CDK 4/6 agents have been proven beneficial. Nevertheless, health-related quality of life from pain and fatigue remains a concern. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine these risks. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2017 were queried. RCTs that mention back pain, pain in arms and legs, arthralgia and fatigue as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Random effects model was applied. Results: A total of 2671 patients with hormone receptor-positive HER2-negative metastatic breast cancer from four phase 3 studies and one phase 2 study were eligible for analysis. The study arms used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant while the control arms utilized placebo in combination with letrozole or fulvestrant. The relative risk (RR) of all-grade back pain was 0.97 (95% CI: 0.81- 1.16; p = 0.76); all-grade pain in arms and legs was 0.98 (95% CI: 0.74- 1.30; p = 0.90); all-grade arthralgia was 0.98 (95% CI: 0.75- 1.27; p = 0.88); and all-grade fatigue was 1.35 (95% CI: 1.20- 1.52; p < 0.0001). The RR of high-grade back pain was 1.47 (95% CI: 0.51- 4.23; p = 0.46); high-grade pain in arms and legs was 0.12 (95% CI: 0.02- 0.73; p = 0.02); high-grade arthralgia was 1.14 (95% CI: 0.40- 3.26; p = 0.79); and high-grade fatigue was 3.06 (95% CI: 1.41- 6.61; p = 0.004). Conclusions: Patients on CDK4/6 inhibitor-based regimens experienced a significant increase in all-grades of fatigue with a relative risk of 3.06 for grade 3 and 4 fatigue whereas they noted a decrease in high-grade pain in the arms and legs favoring CDK 4/6 inhibitor based regimens.