e18284 Background: CDK4/6 inhibitors are proven to be beneficial in patients with hormone receptor-positive HER2-negative breast cancer. Studies have suggested an increased risk of gastrointestinal (GI) events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the risk of GI and hepatic toxicities. Methods: We systematically conducted a comprehensive literature search using MEDLINE and EMBASE databases through January 1, 2017. RCTs that mention GI symptoms and/or elevation of liver enzymes 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). Results: Five RCTs with a total of 2021 patients were eligible for analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, and ribociclib-letrozole while the control arm used placebo with letrozole or fulvestrant. The relative risks of all-grade elevated AST was 2.6 (95% CI: 1.15–5.86; p = 0.02); all-grade elevated ALT: 2.82 (95% CI: 1.25–6.36; p = 0.01); all-grade stomatitis: 3.32 (95% CI: 2.09-5.28; p < 0000.1); all-grade nausea: 1.79 (95%CI: 1.25-2.58; p = 0.002); all-grade vomiting:1.55 (95% CI: 0.92-2.63; p = 0.10); and all-grade diarrhea: 1.59 (95% CI 1.28-1.98; p < 0.0001). The relative risks of high-grade elevated AST was 3.08 (95% CI: 1.42–6.67; p = 0.004); high-grade elevated ALT: 7.2 (95% CI: 2.81–18.43; p < 0.0001); high-grade stomatitis: 2.01 (95% CI: 0.22-18.02; p = 0.53); high-grade nausea: 0.76 (95%CI: 0.12-4.78; p = 0.77); high-grade vomiting: 0.88 (95% CI: 0.19-4.13; p = 0.87); and high-grade diarrhea: 1.23 (95% CI 0.52-2.92; p = 0.64). Conclusions: Our meta-analysis demonstrated that CDK 4/6 inhibitor-based regimens are associated with a higher risk of all-grade and high-grade elevated AST and ALT. Moreover, the regimen is associated with increased risk of all-grade stomatitis, nausea and diarrhea. Recognizing these adverse effects may help clinicians in delivering proper supportive care and thereby enhancing patients’ quality of life.