Progression of chronic kidney disease (CKD) in diabetic patients can occur through enhanced hypothalamic-pituitary-adrenal (HPA) axis activity. The purpose of our study was to determine whether HPA axis activity influences the prevalence of CKD in patients with type 2 diabetes mellitus. Seventy-seven diabetic patients (mean age, 60 years) were enrolled. CKD was defined by K/DOQI criteria, and serum cortisol level was measured after the 1 mg overnight dexamethasone suppression test (F-DST). F-DST values were significantly negatively correlated with estimated glomerular filtration rate (eGFR), and significantly positively correlated with cystatin C level and spot urine albumin to creatinine ratio in simple and multiple regression analyses. The subjects were divided into 3 groups (low, middle, and high) according to the F-DST, and the odds for CKD were 8.7-fold (95% confidence interval 2.56 to 29.6, P=0.01) and 12.5-fold (95% confidence interval 3.3 to 47.9, P<0.001) higher in subjects in the middle and high groups than those in the low group, respectively. In multivariate regression analysis, subjects in the middle group and high group (compared to those in the low group) had 13.0-fold (95% confidence interval, 2.9 to 58.8 and P=0.001) and 14.7-fold (95% confidence interval, 2.8 to 78.5 and P=0.002), respectively, higher risk for CKD. In conclusion, F-DST values have a relationship with decreased eGFR and increased cystatin C or albumin excretion involved in CKD, and enhanced HPA axis activity may be an independent risk factor for CKD in patients with type 2 diabetes mellitus.