·AIM: To evaluate correlation of cystatin-C (Cys-C) with severity of diabetic retinopathy (DR) and acute phase reactants, including erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein(hs-CRP). ·METHODS: All diabetic patients who were referred for diabetic retinopathy (DR) screening during 1mo were enrolled. Demographic data were recorded. All patients have undergone full ophthalmic exam. At the same day, all patients were tested for hemoglobin A1c (HbA1c), ESR,hs-CRP,and Cys-C serum levels. · RESULTS: Sixty seven diabetics were enrolled, including 19 (28.3%) without retinopathy, 22 (32.8%) non - proliferative retinopathy, and 26 ( 38. 8%) proliferative retinopathy patients. The mean age, sex distribution, mean duration of diabetes, prevalence of hypertension and dyslipidemia, smoking status and HbA1c levels were not significantly different among the three groups. The mean levels of Cys - C increase significantly as retinopathy progress [1.1 ± 0. 48; 1. 22 ± 0.38;1.71 ± 0.92 (P=0.007), respectively]. In multiple regression analysis, just Cys - C was significantly associated with severity of DR (P=0.025). ·CONCLUSIONS: This study revealed that serum levels of Cys-C increase while DR progress independently of acute phase reactants. Therefore, it could be used as an associated marker by primary care physicians to distinguish patients at higher risk of severe DR. Larger randomized studies are warranted to confirm findings. Reviewing physiological role of the Cys-C, we proposed that the Cys-C may be a protective response to catalytic stress rather than being a pathogenic factor in microangiopathies.