Background: Hepatitis C (HCV) and diabetes mellitus (DM) are major health burden with various systemic complications. Both affect the kidney with increasing the incidence of progression to end stage renal disease. Aim: Usefulness of tumor necrosis factor (TNF), high-sensitivity CRP (hs-CRP) and interleukin-18 (IL-18) as differentiating markers of proteinuria in HCV diabetic patients. Methods: Eighteen as control and 72 patients with DM were enrolled. Diabetic patients were divided into 4 equal groups; diabetic patients with microalbuminuria negative for HCV (n=18), positive for HCV (n=18), diabetic patients with macro-albuminuria negative for HCV (n=18), positive for HCV (n=18). TNF, hs-CRP and IL-18 were measured in all groups. Results: TNF was not useful for distinguishing microalbuminuria (174.61 ±64.89 vs. 229.33 ±101.31 pg/mL; p=0.093) or macroalbuminuria (69.78 ±22.34 vs. 78.00 ±20.57 pg/mL; p=0.259) in HCV diabetic patients. The hs-CRP had a paradox relationship where higher levels were found in HCV diabetic patients with microalbuminuria (6.42 ±0.76 vs. 4.43 ±0.70 mg/L; p=0.001) unlike those with macroalbuminuria (5.25 ±0.69 vs. 6.72 ±1.56 mg/L; p=0.003). IL-18 increased in microalbuminuria (619.72 ±72.53vs 148.54 ±5.69 mg/L; p=0.001) or macro-albuminuria (609.22 ±52.05 vs. 352.44 ±12.33 pg/mL; p=0.001) in HCV diabetic patients. Conclusion: IL-18 is a promising.