Objective:?Coronary Slow Flow Phenomenon (CSFP)?is a patho[*通讯作者（Corresponding author）,E-mail: zhangxuezhi@qdyhospital.cn ]logical condition characterized by delayed coronary blood flow in the absence of significant stenosis on coronary angiography, which predisposes patients to angina pectoris and cardiovascular events. Current diagnosis relies heavily on invasive investigations, and simple, effective non-invasive predictive tools are lacking. This study aimed to investigate the expression level of serum Growth Differentiation Factor-15 (GDF-15) in CSFP and evaluate its predictive value, with the goal of providing an alternative to the current diagnostic paradigm dependent on invasive coronary angiography (the current gold standard). Methods:?Patients undergoing coronary angiography at the Affiliated Hospital of Qingdao University (December 2023–June 2024) were enrolled. Those with angiographically normal coronary arteries were assigned to the control group (n = 42), while patients exhibiting delayed coronary flow without significant stenosis comprised the CSFP group (n = 69). Clinical data were collected for all participants. Pre-angiography serum growth differentiation factor-15 (GDF-15) levels were measured using ELISA. Logistic regression and receiver operating characteristic (ROC) curve analyses assessed the association between GDF-15 levels and CSFP risk. Results:?GDF-15 levels were significantly higher in the CSFP group versus controls [median (IQR): 957.01 (716.27, 1373.16) ng/L vs. 745.14 (585.43, 812.41) ng/L;?*z*?= –4.14,?P?< 0.001]. Both univariate and multivariate logistic regression (adjusted for body mass index and other confounders) showed that each 1-unit increase in ln(GDF-15) (corresponding to a ~2.718-fold increase in raw concentration) was associated with a 7.22-fold higher CSFP risk (95% CI: 1.36–38.37,?P?< 0.05). Conversely, each 1 mmol/L increase in HDL-C reduced CSFP risk (OR = 0.19, 95% CI: 0.10–0.36,?P?< 0.05). ROC analysis indicated that GDF-15 alone had an AUC of 0.791 for diagnosing CSFP. Combining GDF-15 with HDL-C increased the AUC to 0.953, improving sensitivity from 57.97% to 91.30%. Conclusion:?Elevated serum GDF-15 levels in CSFP patients establish its potential as a non-invasive early warning biomarker. The combined GDF-15/HDL-C diagnostic model demonstrated substantially improved accuracy, suggesting its utility as a practical clinical screening tool. This approach could reduce dependence on invasive coronary angiography for CSFP detection.