We aim to determine the efficacy and the factors associated with the effectiveness of first-line CDK4/6i (ribociclib or palbociclib) treatment in HR-positive, HER2-negative MBC patients. This is a retrospective, cross-sectional, and descriptive study. Ninety patients with metastatic breast cancer receiving CDK 4/6i treatment from three different oncology clinics were included in this study. Of the patients, 56 (62.2%) received ribociclib, and 34 (37.8%) were administered palbociclib. There was no significant difference between the groups regarding age, gender, comorbidities, ECOG performance status, or menopausal status ( > 0.05). The cut-off values for ER, PR, and Ki-67 levels were determined via ROC curve analysis. These values were found to be 80% for ER levels, 50% for PR levels, and 30% for Ki-67 levels. PFS was significantly longer for patients with ER levels greater than 80% and Ki-67 expression levels less than 30% according to multivariate analysis. Among the patients included in our study, the median PFS was 22.41 months for the patients with Ki-67 levels of 30% and above, while the median PFS was 17.24 months for the patients with ER levels of 80% and below. Among the patients with a combined ER of 80% or less and a Ki-67 of 30% or more, the median PFS was 12.42 months ( < 0.001). This study demonstrates that CDK4/6i therapies led to longer PFS among patients with ER levels greater than 80% and Ki-67 expression levels less than 30%. It is essential to determine which patient group benefits more from first-line CDK4/6is therapy.