Reduced myocardial mechano-energetic efficiency (MEE), estimated as stroke volume/heart rate ratio per g of left ventricular (LV) mass (LVM), and expressed in μl s-1 g-1 (MEEi), is a strong predictor of cardiovascular (CV) events, independently of LV hypertrophy and other confounders, including type II diabetes (DM). Decreased MEEi is more frequent in patients with diabetes. In the present analysis we evaluated the interrelation among MEEi, DM and metabolic syndrome (MetS) in the setting of arterial hypertension. Hypertensive patients from the Campania Salute Network, free of prevalent CV disease and with ejection fraction >50% (n=12 503), were analysed. Coexistence of MetS and DM was ordinally categorized into 4 groups: 8235 patients with neither MetS nor DM (MetS-/DM-); 502 without MetS and with DM (MetS-/DM+); 3045 with MetS and without DM (MetS+/DM-); and 721 with MetS and DM (MetS+/DM+). After controlling for sex, systolic blood pressure, body mass index, relative wall thickness (RWT), antihypertensive medications and type of antidiabetic therapy, MEEi was 333 μl s-1 g-1 in MetS-/DM-, 328 in MetS-/DM+, 326 in MetS+/DM- and 319 in MetS+/DM+ (P for trend <0.0001). In pairwise comparisons (Sidak-adjusted), all conditions, except MetS-/DM+, were significantly different from MetS-/DM- (all P<0.02). No statistical difference was detected between MetS-/DM+ and MetS+/DM-. Both MetS and DM are associated with decreased MEEi in hypertensive patients, independently to each other, but the reduction is statistically less evident for MetS-/DM+. MetS+/DM+ patients have the lowest levels of MEEi, consistent with the alterations of energy supply associated with the combination of insulin resistance with insulin deficiency.