BACKGROUND This study aimed to evaluate the effect of dose reduction of CDK4/6 inhibitors on survival outcomes in postmenopausal patients with HR+ HER2-negative metastatic breast cancer (mBC). METHODS A retrospective cohort study was conducted involving 164 postmenopausal patients with HR+ HER2-negative mBC who received CDK4/6 inhibitors between 2021 and 2024. Clinical parameters were systematically analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated based on dose reduction status. Survival outcomes were estimated using the Kaplan-Meier method, and independent prognostic factors were identified through multivariate Cox regression analysis. RESULTS The median age was 61 years, with a median follow-up of 23.5 months. The median PFS was 23.3 months, while median OS was not reached. Dose reduction occurred in 45 patients (27%), who exhibited significantly worse survival (PFS HR: 1.67, 95% CI: 1.02-2.72, p = 0.042; OS HR: 2.54, 95% CI: 1.34-4.83, p = 0.004). Dose reduction and liver metastases were independent risk factors for shorter PFS and OS, while treatment in later lines was associated with shorter PFS. CONCLUSION Dose reductions in CDK4/6 inhibitors were associated with worse survival outcomes in postmenopausal HR+ HER2- mBC patients. Future biomarker-driven studies are needed to guide personalized dose adjustments and optimize treatment efficacy.