Background: Abemaciclib and Palbociclib are both CDK4/6 inhibitors and its combination use with hormone drugs prolonged progression-free survival in estrogen receptor positive metastatic breast cancer. Both are not yet directly compared in terms of efficacy, adverse events, and discontinuation rates due to the adverse events. MonarchE trial evaluated adverse events of Abemaciclib as follows; 81.3% had diarrhea and 41.3% had neutropenia, whereas PALOMA-3 trial showed 92% of neutropenia (74% had Grade3 neutropenia) in patients receiving Palbociclib. Of the patients who received CDK4/6 inhibitors in our institutions, we compared the difference of rates in adverse events, and we discussed the importance of acknowledging the risks between the two drugs. Methods: We reviewed a total of 169 patients comprising 53 with Abemaciclib and 116 with Palbociclib from 2017 to 2023 at two institutions as 1st – 3rd line treatments. The year of prescription, treatment line, age and the adverse event which led to treatment discontinuation was analyzed. Results: All patients were women, and the median age was 57 (29-84). The patients who received treatment as 1^st, 2^nd, 3^rd lines were 98, 49, and 22, respectively. Twenty-six patients received cytotoxic chemotherapy before CDK4/6 inhibitors. Patients diagnosed as de-novo stage IV patients were 108, while 61 had recurrent tumors. Treatment discontinuation due to adverse events of CDK4/6 inhibitors were 41 (24%) in which 14 (8.3%) had diarrhea and 20 (12%) had neutropenia. We conducted a multivariate analysis setting the endpoint as any adverse events resulting to treatment discontinuation. Abemaciclib (HR=1.20 p=0.01), the first prescription date (2017-19 vs 2020-23, HR:0.84 p=0.02), and patients with metastatic breast cancer at first diagnosis (HR:1.15 p=0.039) significantly affected adverse events leading to treatment discontinuation. Patients receiving Abemaciclib discontinuedecause of diarrhea more than patients receiving Palbociclib (p<0.001 HR:1.28), whereas patients receiving Palbociclib discontinued treatment because of neutropenia more than patients receiving Abemaciclib (HR=1.13 p=0.036). Conclusions: The type of CDK4/6 inhibitor, de-novo Stage IV or recurrent breast cancer, and the year of treatment initiation led to differences in safety of CDK4/6 inhibitor treatment. Abemaciclib leads to treatment discontinuation more than Palbociclib with the most reported adverse event; diarrhea. In addition, the risk of adverse events differs from the year of treatment initiation, which suggests that management of adverse events is improving over time. Thus, it is crucial to accomplish the management of adverse events when starting Abemaciclib which has higher treatment discontinuation rates due to adverse events.