Background: Breast cancer is the most common malignancy in females worldwide and is the second cause of cancer related mortality after lung cancer. Outcome of treatment of metastatic breast cancer is still controverse , up till now no clear data about effect of ki67 an PR status on treatment outcome. we aimed to determine the prognostic and predictive value of Ki67 and PR status among metastatic breast cancer patients on CDK4\6 inhibitor treatment. Patients and Methods: This observational prospective cohort study was conducted on 50 female patients with hormone- receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) from January 2022 till May 2024 with median follow up period 19.88 months (10.89 28.09), treated and followed up at the Department of Medical Oncology, faculty of medicine, Zagazig University. Ki67 and progesterone receptor status were assessed by immunohistochemistry in primary tumor samples before starting the treatment. Results: Considering biobsy from primary tumour, IDC was the commonest pathological type (90.0%), Grade II was the commonest (64.0%) followed by Grade III (28.5%), ER positive was the commonest (93.0%), PR ≥ 20 % was (60.0%), Ki67 ≥ 14 % was (62.0%), The biobsy from metastatic site showed that, all the studied group were ER positive (100%), PR ≥ 20 % was (62%) and ki67 Low (<14%) in (48%) of the studied group, Concerning survival rate of the whole group, the median follow up was 19.88 months ranging (10.89 28.09) months. The 5-years OS rate was (95.5%) with the median not reached. There was statistically significant relation between PR and KI67 status and 5 years OS rate. PR ≥20% was associated with statistically significant longer OS rate at 5 years (100% vs 87.5%) (p=0.009) and the median survival estimate not reached. Ki67 ≥14% had marginally significant shorter OS rate at 5 years than those with Ki67 <14% (91.3% vs 100%) and the median not reached(p=.026). As regard PFS, the median survival was 10.56 months and 8-month PFS rate was 88 %, and 32% of patients remained progression-free at 12 months as CDK4/6 inhibitors was not used in first line treatment in this study. There was statistically significant correlation between PR, KI67(proliferation index) and HER-2 status.. PR ≥20% was associated with statistically significant longer PFS rate at 12 months (45.2% vs 10.5%) and the median survival estimate was (11.23 vs 10.50) (p 0.032). Also, KI67<14% was associated with statistically highly significant longer PFS rate at 12 months (58.3% vs 7.7%) and the median survival estimate was (10.36 vs 12.43) (p < 0.001). Conclusion: Outcome of treatment of metastatic breast cancer is still controverse , Ki-67 and progesterone receptor status may be reliable predictors of response to CDK4/6 inhibitors in metastatic breast cancer, highlighting the need for further research to identify robust biomarkers. Alternative predictive biomarkers and patient stratification strategies are therefore crucial for optimizing treatment selection and improving outcomes.