Background <p>The identification of reliable biomarkers for the Cyclin-dependent kinase (CDK) 4/6 inhibitor efficacy is crucial for optimizing treatment strategies in patients with advanced hormone receptor-positive (HR+) /human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This study aimed to evaluate the prognostic value of ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET/CT) parameters in patients treated with CDK4/6 inhibitor abemaciclib with endocrine therapy.</p> Methods <p>We conducted a retrospective study of patients with advanced HR+/HER2- breast cancer who received abemaciclib plus endocrine therapy and underwent ¹⁸F-FDG PET/CT examination. Parameters such as maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of PET/CT and clinicopathological parameters were assessed.</p> Results <p>A total of 72 consecutive patients were included. Most patients (79.2%) received first-line therapy. 52.8% patients received aromatase inhibitors and 47.2% received fulvestrant. The median progression-free survival (PFS) was 16.6 (95% <i>CI</i>: 11.3–22.0) months, while overall survival (OS) was not reached at a median follow-up of 15.4&#xa0;months (interquartile range: 9.4–20.9). High baseline TLG (≥ 96.95&#xa0;g) and low progesterone receptor (PR) expression (&lt; 20%) were associated with significantly shorter PFS. A prognostic model incorporating TLG and PR expression effectively stratified patients into distinct risk groups for both PFS and OS.</p> Conclusion <p>High baseline TLG on PET/CT and low PR expression were identified as adverse prognostic factors in patients with advanced HR+ /HER2- breast cancer treated with the CDK4/6 inhibitor abemaciclib in combination with endocrine therapy.</p> Trial registration <p>ClinicalTrails.gov NCT05613270. Registered 28 February 2012, partly retrospectively registered.</p>