Sirtuins (SIRTs) are master metabolic regulators with protective roles against obesity and obesity-associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) and type-2 diabetes. We aimed to ascertain whether there is a relationship between serum SIRT1 and liver steatosis severity in obese patients. Seventy-two obese patients (BMI ≥ 30 kg/m(2)), 18 males and 54 females, mean age 39.66 ± 12.34 years, with ultrasonographic evidence of NAFLD, were studied. BMI, transaminases, insulin, HOMA-index, HbA1c, body composition (DXA), plasma SIRT1 levels (ELISA) and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were evaluated. Thirty healthy lean patients were included as controls. SIRT1 was significantly lower in severe liver steatosis obese group compared to the mild steatosis group, both had lower SIRT1 plasma values compared to control lean patients (P = 0.0001). SIRT1 showed an inverse correlation with liver steatosis and HbA1c in univariate analysis (ρ = -0.386; P = 0.001; ρ = -0.300; P = 0.01, respectively). Multiple linear regression analysis showed that liver steatosis was the independent correlate of SIRT1 even after adjustment for potentially relevant variables (β = -0.442; P = 0.003). Serum SIRT1 might be a novel clinical/biochemical parameter associated with fat liver infiltration. Further studies in larger cohorts are warranted.