Purpose: Impaired cardiac sympathetic innervation has been reported in diabetic patients with heart failure (HF) compared to non-diabetic patients, but mechanisms have not been investigated. The aim of this study was to evaluate whether insulin resistance is associated with impaired cardiac sympathetic innervation in patients with HF. Methods: 102 patients (87% male; age 67±9 years) with systolic HF (mean ejection fraction 31±7%), of whom 49 diabetics, underwent in the same day Iodine123 meta-iodobenzylguanidine (MIBG) scintigraphic study and blood sampling for insulin and fasting glucose measurement. To assess insulin sensitivity Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR) index was calculated using the formula \[fasting Glucose (mmol/L) x fasting Insulin (mU/L)/22.5\] (normal values <2.5). From MIBG scintigraphy the early and late heart-to-mediastinum (H/M) ratios were calculated. Results: Sixty-seven patients (66%) were insulin resistant (IR). In these patients early (1.62±0.19 vs 1.81±0.23; p<0.001) and late (1.46±0.19 vs 1.61±0.29; p=0.001) were significantly lower compared to 35 (34%) patients without IR. No differences were observed for age, ejection fraction, NT-proBNP and HbA1c between the two groups. When patients were divided in a group with diabetes mellitus (DM; 48%), a group with IR without DM (26.5%) and a group without IR and without DM (25.5%), significant differences were found among groups by ANOVA test (early H/M p=0.001; late H/M p=0.021) with lowest values in DM patients (early H/M 1.62±0.22; late H/M 1.45±0.21), intermediate values in non-DM/IR patients (early H/M 1.67±0.17; late H/M 1.53±0.20) and highest values in subjects without diabetes and without IR (early H/M 1.82±0.21; late H/M 1.61±0.29). In the whole population a significant inverse correlation was found between HOMA-IR and H/M ratio (r=-0.25; p=0.013). Conclusions: Cardiac sympathetic innervation correlates with the status of insulin sensitivity in patients with HF. These findings provide new insights into mechanisms of adverse prognosis in patients with DM and HF.