BACKGROUND: Cell-cycle protein-dependent kinase 4 and 6 inhibitors (CDK4/6is) in combination with endocrine therapy (ET) are widely used in patients with early and advanced breast cancer (BC). CDK4/6is also lead to numerous side effects. This study aims to elucidate the relationship between CDK4/6is and hepatotoxicities. RESEARCH DESIGN AND METHODS: As of 31 March 2024, we conducted a systematic search of PubMed, Embase, and the Cochrane Library databases, as well as several oncology conference proceedings. We included 20 randomized controlled trials (RCTs) with 24,342 breast cancer (BC) patients and 400 cases from the FDA Adverse Event Reporting System (FAERS). Fixed-effect and random-effect models were used to calculate odds ratios (ORs) of hepatotoxicity in the RCTs, while Reporting Odds Ratios (RORs) were calculated for the FAERS data. RESULTS: Overall, CDK4/6 inhibitors (CDK4/6is) were associated with significant hepatotoxicities compared to controls (OR = 1.76, 95%CI 1.40-2.22, I CONCLUSIONS: CDK4/6is increase the risk of hepatotoxicities in patients with BC. Palbociclib, ribociclib, and abemaciclib caused liver damage, while dalpiciclib did not. The most common manifestations were elevated ALT and AST levels.