Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) prolonged the progression-free survival (PFS) in hormone receptor (HR) positive HER2 negative metastatic breast cancer (MBC). Palbociclib is the only CDK4/6 inhibitor approved in Mainland China. Aims: This retrospective study investigated the clinical efficacy of palbociclib with ET in real-world practice. Methods: This study was a retrospective observational study including the MBC patients who received the ET with palbociclib in two centers in China. We analyzed the medical records for treatment outcomes and the PFS curves were derived using the Kaplan–Meier method. Results: 69 patients were included. The overall response rate (ORR) was 10.1%, and clinical benefit rate (CBR) was 78.3%. The median PFS was 12.8 months (95% confidence interval [CI]: 10.1–15.5). A longer PFS was observed in the patients with bone only metastasis, no liver metastases, no previous palliative chemotherapy, no previous palliative ET, endocrine sensitivity. 19 patients (27.5%) had reduced the dose of palbociclib according to physician’s decision, and dose reduction didn’t affect the clinical efficacy of the combined treatment. Conclusion: ET combined with palbociclib was effective and well tolerated in HR positive HER2 negative MBC patients in real-world setting.