Background: This retrospective study addresses the question of whether real-world treatment with CDK4/6 inhibitors in combination with Endocrine Therapy (ET) for advanced hormone receptor positive (ER+) HER2 negative breast cancer yields similar benefits as reported by the major clinical trials: PALOMA-2 and MONALEESA-3. Methods: This study used the nationwide electronic health record-derived-Flatiron Health de-identified database to test the benefits demonstrated in major clinical trials on MBC patients under treatment with CDK4/6 + Letrozole (PALOMA-2) or CDK4/6 + Fulvestrant (MONALEESA-3). Regarding PALMOMA-2, a total of 1,774 patients with ≥ 3 months of follow-up received either CDK4/6 + Letrozole (n=1,277) or Letrozole alone (n=497) as the first line of treatment between February 3, 2015, and November 02, 2021. To test the benefits reported in MONALEESA-3, 1,187 patients are selected who were treated with either CDK4/6 + Fulvestrant (n=786) who received no or up to 1 line of prior ET or Fulvestrant alone (n=401). We conducted inverse probability weighting to balance the baseline demographic and clinical characteristics between patients in all subgroups. Kaplan-Meier method and Cox proportional hazards were used to test for the association of CDK4/6 treatment on rwPFS as the primary outcome and rwOS as the secondary outcome while adjusting for patient characteristics (e.g., age, race, ECOG PS value, health insurance, etc). Results: The real-world analysis of PALOMA-2 showed similar results as demonstrated in the clinical trials. The findings showed receiving CDK4/6 + Letrozole as the first-line treatment was associated with significantly longer median PFS compared to receiving Letrozole alone (28.3 vs 18 months; hazard ratio [HR], 0.57; 95% CI, 0.46–0.69; P < 0.0001). Median OS was 56.5 months for the group with first line CDK4/6 + Letrozole and 50.4 months for the group with Letrozole alone (HR=0.76, 95% CI, 0.61–0.93, P-value = 0.01). Analysis of real-world practices of MONALEESA-3 also endorsed the results reported from the trial. Median PFS was 17.5 months for the group treated with CDK4/6 + Fulvestrant who received no or up to 1 line of prior ET, while it was about 14.3 months for patients treated with only Fulvestrant (HR=0.64, 95% CI, 0.52–0.80, P-value < 0.0001). Consistent OS benefit was observed in patients treated with CDK4/6 + Fulvestrant compared to those treated with only Fulvestrant (44.72 vs 35.83 months; hazard ratio [HR], 0.70; 95% CI, 0.52–0.94; P < 0.0001). Conclusions: Consistent with what was reported in major clinical trials: PALOMA-2 and MONALEESA-3, receiving CDK4/6 inhibitor plus endocrine therapy (Letrozole or Fulvestrant) was associated with improved progression free survival compared with patients treated with ET alone in this “real-world” population of patients with HR+/HER2− MBC.