Background: The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET<sub>A</sub> (T/C in exon 6, H323H) could predispose carriers to heart failure (HF). Methods: Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) ≤40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26). Results: The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET<sub>A</sub> variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET<sub>A </sub>polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = –0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = –0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis. Conclusions: The ET-1 Lys198Asn and ET<sub>A</sub> receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.