Objective To analyze diagnostic value of serum cystatin C (CysC), β2 microglobulin (β2MG) combined with endogenous creatinine clearance rate (Ccr) for early renal injury in patients with type 2 diabetes mellitus (T2DM).Methods A retrospective collection was performed on 147 T2DM patients who were admitted to the hospital from January 2017 to March 2019. According to urinary albumin excretion rate (UAER), they were divided into simple T2DM group (n=62), microalbuminuria group (n=59) and clinical proteinuria group (n=26). CysC, β2MG and Ccr in peripheral blood were compared. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of the three alone and their combination for early renal injury in T2DM patients. Results UAER, CysC and β2MG in simple T2DM group were lower than those in microalbuminuria group and clinical proteinuria group (P＜0.05), while Ccr in simple T2DM group was higher than that in microalbuminuria group and clinical proteinuria group (P＜0.05). UAER, CysC and β2MG in microalbuminuria group were lower than those in clinical proteinuria group, while Ccr in microalbuminuria group was higher than that in clinical proteinuria group (P＜0.05). The area under curve (AUC) of CysC for diagnosis of early renal injury of T2DM was 0946. When Yoden index was the greatest, the corresponding sensitivity and specificity were 9014% and 9032%, followed by Ccr (AUC=0945). When Yoden index was the greatest, the corresponding sensitivity and specificity were 8475% and 9194%, respectively. The diagnostic efficiency of the three combination for early renal injury of T2DM was the highest. AUC was 0951. When Yoden index was the greatest, the corresponding sensitivity and specificity were 9214% and 9232% respectively. Conclusion The early renal damage of T2DM is accompanied with increase of CysC and β2MG and decrease of Ccr. The changes of the three are related to progression of renal damage, which collectively participate in process of T2DM renal damage. In single index, diagnostic efficiency of CysC is the highest for early renal damage in T2DM. The diagnostic efficiency of the three combination is superior to single diagnosis.