Objective To investigate the changes and clinical significance of high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (CEC) in patients with diabetes mellitus. Methods Patients with diabetes attending West China Hospital of Sichuan University between January 2022 and June 2024 and healthy physical examination subjects during the same period (serving as the control group) were selected. The diabetic group was further divided into high glycated hemoglobin (HbA1c) with normal fasting plasma glucose (FPG) group and high HbA1c with high FPG group. CEC levels were compared among groups, correlations between CEC and glucose/lipid metabolism indices were analyzed, and binary logistic regression was used to assess the independent association between CEC and diabetes. Results A total of 260 patients with diabetes were enrolled, and 203 patients in the control group. Among them, there were 88 cases in the high HbA1c with normal FPG group and 172 cases in the high HbA1c with high FPG group. Compared with the control group [30.52% (26.99%, 32.25%)], CEC levels in the high HbA1c with normal FPG group [26.01% (23.81%, 28.21%)] and the high HbA1c with high FPG group [24.02% (17.40%, 27.49%)] were significantly lower (P<0.001). At the same HbA1c stratum, higher FPG was associated with lower CEC; at the same FPG stratum, higher HbA1c was associated with lower CEC. Correlation analysis showed that CEC was negatively correlated with FPG (r=?0.434, P<0.001) and HbA1c (r=–0.444, P<0.001), positively correlated with apolipoprotein A-Ⅰ (r=0.363, P<0.001), positively correlated with HDL-cholesterol (r=0.103, P=0.028). Multivariate logistic regression analysis showed that CEC was still associated with diabetes [odds ratio=0.785, 95% confidence interval (0.732, 0.842), P<0.001]. Conclusions HDL-mediated CEC is significantly impaired in patients with diabetes, and the degree of impairment worsens with increasing blood glucose and HbA1c levels. Routine lipid parameters cannot reflect HDL function, and CEC may serve as an independent indicator for evaluating the risk of diabetes and its cardiovascular complications.