Abstract: Objective To investigate the expression of cysteine-rich protein 61 (CYR61) and sortilin in peripheral blood of patients with diabetic lower extremity arterial disease (DLEAD) and their correlation with disease severity. Methods A total of 150 DLEAD patients who were admitted to the Fourth Affiliated Hospital of Xinjiang Medical University from January 2021 to December 2024 were enrolled and set as a LEAD group. According to the Fontaine classification, the patients were divided into three groups: stage Ⅰ (n=63), stage Ⅱ (n=48), and stages Ⅲ—Ⅳ (n=39). Additionally, another 150 patients with simple type 2 diabetes mellitus (T2DM) were selected at a 1∶1 ratio and set as a non-LEAD group. The levels of CYR61 and sortilin were measured by enzyme-linked immunosorbent assay (ELISA). Logistic regression was conducted to analyze the relationships between these markers and the occurrence and severity of DLEAD. Receiver operating characteristic (ROC) curves were plotted to evaluate their diagnostic value and their correlation with disease severity. Results As the Fontaine stage progressed, the duration of diabetes was extended, while ankle-brachial index (ABI) levels were decreased, CYR61 and sortilin levels were gradually increased (P<0.05). The DLEAD groups showed increases in fasting blood glucose, hemoglobin A1c, and low-density lipoprotein cholesterol levels and decreases in high-density lipoprotein cholesterol levels, compared with the non-LEAD group (P<0.05). A longer duration of diabetes, higher hemoglobin A1c, and higher CYR61 and sortilin levels were independent risk factors for DLEAD, while an elevated ABI was an independent protective factor (P<0.05). A longer duration of diabetes and higher CYR61 and sortilin levels were independent risk factors for the aggravation of DLEAD, whereas an elevated ABI was an independent protective factor (P<0.05). The area under the curves (AUCs) for the combined diagnosis of DLEAD using CYR61 and sortilin (0.938) was higher than either marker alone (0.856 and 0.877, respectively) (P<0.05). The AUC for the combined prediction of DLEAD severity using peripheral blood CYR61 and sortilin was 0.908, which is higher than either marker alone (0.813 and 0.829, respectively) (P<0.05). Conclusions Elevated levels of peripheral blood CYR61 and sortilin are closely associated with the occurrence and severity of DLEAD. Their combined use has high clinical value for diagnosing DLEAD and evaluating disease severity.