Increasing evidence suggests that liver fibrosis in subjects with non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). It has also been shown that NAFLD is associated with decreased myocardial glucose uptake in subjects with type 2 diabetes. However, the association between myocardial glucose uptake and liver fibrosis is unsettled. To elucidate this issue, we aimed to investigate the association between liver fibrosis severity and insulin-stimulated myocardial glucose metabolic rate in 57 subjects without coronary heart disease exhibiting different glucose tolerance status. Myocardial metabolic rate of glucose (MRGlu) was assessed using dynamic cardiac 18F-FDG PET combined with euglycemic hyperinsulinemic clamp, which allows to assess peripheral insulin sensitivity normalized for lean body mass (MFFM) and to standardize metabolic and hormonal conditions during PET. Liver fibrosis severity was estimated by the fibrosis-4 index (FIB-4), one of the most widely used non-invasive fibrosis test, which uses as variables age, levels of aspartate aminotransferase (AST), levels of alanine aminotransferase (ALT), and platelet counts. According to FIB-4 index, subjects were stratified into four groups: lowest risk of fibrosis (<1.3; n=37); low risk of fibrosis (≥1.3 to <1.67; n=12); moderate risk of fibrosis (≥1.67 to <2.67; n=4); high risk of fibrosis (≥2.67; n=4). As compared with subjects with lowest risk of liver fibrosis, those with high risk of advanced fibrosis exhibited a decrease in myocardial MrGlu (21.7+11 vs 4.6+4.3 mmol/min/100g; p=0.005). No significant differences in glycemic and anthropometric parameters, in whole body insulin sensitivity, and in blood pressure were found between groups. Univariate correlations showed that FIB-4 index was significantly negatively correlated with myocardial MRGlu (r=-0.320, p=0.01), and positively correlated with waist circumference (r=0.299, p=0.02). In a multivariable regression analysis, the only variable significantly associated with FIB-4 index was myocardial MrGlu (r=-0.286; p=0.003) explaining the 28.6% of its variation. These data suggest that an impairment of insulin-stimulated myocardial glucose metabolism is associated with higher risk of liver fibrosis and may represent an early cardio-metabolic defect heralding future CV events in subjects with NAFLD and advanced fibrosis.