BACKGROUND: The safety profile of CDK4/6 inhibitors has not yet been systemically analysed in the real world. This study aimed to provide a comprehensive understanding of AEs associated with CDK4/6 inhibitors using the FAERS database. METHODS: FAERS data (2014Q1 to 2022Q4) were searched for reports of all FDA-approved CDK4/6 inhibitors across all indications. We used the SMQ generalized search AEs on the PT level. Disproportionality analysis was used to detect safety signals by calculating RORs. RESULTS: Within the standardized MedDRA queries, significant safety signals were found, including those for palbociclib [haematopoietic leukopenia, erythropenia], ribociclib [haematopoietic leukopenia , conduction defects], and abemaciclib [eosinophilic pneumonia, dehydration]. For AEs at the PT level, we found several significant blood and lymphatic system disorders for both palbociclib and ribociclib, such as abnormal full blood count and decreased white blood cell count for palbociclib and anisocytosis, neutropenia for ribociclib. Palbociclib also had high RORs for pseudocirrhosis, stomatitis, oral pain, and alopecia, while ribociclib had high RORs for electrocardiogram PR shortened, sinus arrhythmia, and blood bilirubin abnormal. However, the RORs were significant for abemaciclib in terms of diarrhoea, vena cava thrombosis, thrombophlebitis migrans and pneumonitis. CONCLUSION: CDK4/6 inhibitors differed in their safety profile reports.