Abstract Background Initial treatment for advanced ER-positive/HER2-negative breast cancer involves a CDK 4/6 inhibitor (CDK 4/6i). Recent overall survival (OS) analyses led the Danish Medical Council to exclude palbociclib as preferred option. This study aimed to evaluate the real-world effectiveness of abemaciclib, palbociclib, and ribociclib in a Danish context. Additionally, to compare the inhibitors to identify potential endpoint differences. Material and methods Patients undergoing first or second line CDK 4/6i treatments from January 1st, 2017, until December 31st, 2021 were included. The primary endpoint was progression free survival (PFS). Results Among 2069 Danish patients, 1554 received first line treatment, 515 received second line treatment. In first line, abemaciclib’s median PFS was unreached; palbociclib had a median PFS of 32.0 months (95% CI: 28.9–35.3); ribociclib 42.4 months (95% CI: 35.1–52.9). First-line median OS was 37.8 months (95% CI: 32.5–NA); 49.7 months (95% CI: 44.7–54.1); and 54.4 months (95% CI: 47.9–NA) for abemaciclib, palbociclib and ribociclib, respectively. No significant differences in OS were observed, nor in PFS in second line. Conclusion This study confirms first-line CDK 4/6i effectiveness, with abemaciclib and ribociclib showing prolonged PFS vs. palbociclib. This study could not confirm a ranking of the three CDK 4/6i.