AIMS: Weight excess and insulin resistance predispose to heart failure. High sodium consumption may contribute to the development of cardiac impairment in insulin-resistant individuals by promoting inadequate skeletal muscle microvascular perfusion response to insulin. We sought to investigate the association of dietary sodium reduction with muscle perfusion, insulin sensitivity, and cardiac function in overweight/obese insulin-resistant (O-IR) normotensive subjects. METHODS AND RESULTS: Fifty O-IR individuals with higher than recommended sodium intake were randomized to usual or reduced sodium diet for 8 weeks; 25 lean, healthy subjects served as controls for pre-intervention measurements. Echocardiography and muscle perfusion were performed during fasting and under stable euglycaemic-hyperinsulinaemic clamp conditions. O-IR patients demonstrated subclinical cardiac dysfunction as evidenced by lower left ventricular global longitudinal strain (GLS), e' tissue velocity, and left atrial strain and reduced muscle perfusion. The intervention arm showed improvements in insulin resistance [glucose infusion rate (GIR)], GLS, e', atrial strain, and muscle perfusion in fasting conditions, as well as improved responses of GLS and muscle perfusion to insulin during clamp. Significant interactions were found between the allocation to low-salt diet and improvement in muscle perfusion on change in GIR at follow-up (P = 0.030), and between improvement in muscle perfusion and change in GIR on change in GLS response to insulin at follow-up (P = 0.026). Mediation analysis revealed that the relationship between the reduction of sodium intake and improvement in GLS was mediated by improvements in muscle perfusion and GIR (decrease in beta coefficient from -0.29 to -0.16 after the inclusion of mediator variables to the model). CONCLUSIONS: The reduction of dietary sodium in the normotensive O-IR population improves cardiac function, and this effect may be associated with the concomitant improvements in skeletal muscle perfusion and insulin resistance. These findings might contribute to refining heart failure preventive strategies.