There is limited data on the effect of CDK 4/6 inhibitors in the patients with advanced HR-positive and HER2-low tumors. Here we report real-life data retrospectively collected from 448 patients with ER-positive/HER2-negative advanced breast cancer treated with ribociclib and palbociclib (only both of them reimbursed) plus endocrine therapy from June 2016 to June 2022. The outcome of the patients with HER2-0 (IHC score) and HER2-low (HER2 IHC score1+ and 2+) tumors were compared. 443 of the patients were female (98.9%). Median age was 58 (25-90). While the HER2 IHC score was 0 in 295 of the patients (65.8%), the HER2 IHC score was 1-2 (HER2-low) in 153 patients (34.2%). Median OS could not be calculated at follow-up, with an estimated 71% of patients alive at 36 months. The median PFS was 29.4 months (95 CI, 16.3-42.6). mPFS in the HER2-negative patient group was 27.7 (95% CI, 11.2-44.2) months and there was no significant difference in mPFS for patients receiving palbociclib or ribociclib in this subgroup (p=0.11). There were 117 patients in the IHC 1 positive subgroup of HER2-low patients, and 22 patients had disease progression. mPFS was NE (at 12 months, 82% of patients and at 24 months, 57% of patients were progression free). There were 36 patients in the IHC 2 positive subgroup of HER2-low patients, and 6 patients had disease progression. mPFS was NE (at 12 months, 72% of patients were progression free). No significant difference was found between patient population with HER2-negative, HER2 IHC 1+ and HER2 IHC 2+ and ISH negative tumors in terms of mPFS (p=0.163). In addition, when evaluated separately in IHC 1 positive and IHC 2 positive subgroups, there was no significant difference in terms of mPFS in those treated with palbociclib and ribociclib (p=0.50 and p=0.70, respectively). Although the number of patients decreased when subdivided in our study, real-life data showed that HER2-low expression did not show a statistically significant impact on survival in patients treated with ribociclib and palbociclib in the metastatic first-line setting.