Diabetic kidney disease (DKD) is a major complication of diabetes, and serves as an important cause of end-stage renal disease (ESRD). The role of chronic inflammation in DKD is becoming widely accepted. Pancreatic stone protein/regenerating protein (PSP/reg) is a secretory protein, which is elevated in blood during infected conditions and organ failure. The aim of this study was to investigate the relationship between serum PSP/reg and DKD in patients with type 2 diabetes (T2DM). A total of 120 subjects which includes newly diagnosed T2DM patients, diabetes patients without DKD, DKD patients, as well as healthy controls were enrolled in this study. Serum PSP/reg levels were significantly higher in DKD subjects compared with those of healthy controls (p < 0.001), newly diagnosed T2DM (p < 0.001) and diabetes patients without DKD (p < 0.001). PSP/reg levels correlated positively with glycated hemoglobin (HbA1c) (p < 0.001) and serum creatinine (p < 0.001). Meanwhile, serum PSP level was negatively correlated with estimated glomerular filtration rate (eGFR) (p < 0.001). The area under the curve (AUC) for presence of DKD was 0.854. In conclusion: PSP/reg levels are significantly up-regulated in DKD patients and might be related to renal injury. A follow-up study with a large cohort is needed.