OBJECTIVE: To explore the correlation between serum interleukin-22 (IL-22) and interleukin-27 (IL-27) levels and vasculopathy in patients with diabetic nephropathy (DN). METHODS: A total of 104 DN patients treated at the Shanxi University of Traditional Chinese Medicine Affiliated Hospital were selected as the observation group, with another 104 healthy individuals, serving as the control group in this retrospective study. The baseline data and the serum levels of IL-22 and IL-27 were compared between the two groups. The observation group was divided into three subgroups based on their urinary albumin excretion rate (UAER): clinical albuminuria group (microangiopathy, 29 patients), microalbuminuria group (51 patients), and normal albuminuria group (24 patients). Logistic regression was used to analyze the factors influencing the occurrence of microangiopathy. According to whether they had major adverse cardiovascular events (MACE) during 6-month follow-up, the DN patients were divided into a MACE group (n = 39) and a non-MACE group (n = 65). The serum levels of IL-22 and IL-27 were then compared between the two groups. The clinical utility of IL-22 and IL-27 in the assessment of microangiopathy and prognosis was evaluated through receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to the control group, the observation group exhibited significantly higher serum levels of fasting blood glucose, glycated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein, uric acid, blood creatinine, cystatin C, IL-22 and IL-27, but lower glomerular filtration rate (all P<0.05). There were significant differences among different albuminuria groups in terms of duration of disease, serum levels of fasting blood glucose, low-density lipoprotein, cystatin C, IL-22, IL-27, and glomerular filtration rate (all P<0.05). Correlation analysis showed that the serum levels of IL-22 and IL-27 were positively correlated with the duration of disease and serum levels of fasting blood glucose, low-density lipoprotein, uric acid, blood creatinine and cystatin C. However, they were negatively correlated with glomerular filtration rate (P<0.05). The logistic regression analysis indicated that the glomerular filtration rate and serum levels of cystatin C, IL-22, and IL-27 were independent risk factors for the occurrence of microangiopathy. Compared to non-MACE group, the MACE group presented with higher serum IL-22 and IL-27 levels. ROC curve analysis showed that the AUC (Area Under the Curve) for combined detection (>0.9) of serum IL-22 and IL-27 levels was higher than that (>0.8) for each alone in assessing microangiopathy in DN patients. Additionally, the AUC for using serum IL-22 and IL-27 levels, whether individually or in combination, exceeded 0.7 when evaluating patient prognosis. CONCLUSION: Elevated serum IL-22 and IL-27 levels are closely associated with the severity of the DN and can serve as auxiliary indicators for assessing microangiopathy and prognosis in DN patients.