Our previous work showed the presence of endothelin-1 (ET-1) receptors, ET and ET, in human vascular endothelial cells (hVECs). In this study, we wanted to verify whether ET-1 plays a role in the survival of hVECs via the activation of its receptors ET and (or) ET (ETR and ETR, respectively). Our results showed that treatment of hVECs with ET-1 prevented apoptosis induced by genistein, an effect that was mimicked by treatment with ETR-specific agonist IRL1620. Furthermore, blockade of ETR with the selective ETR antagonist A-192621 prevented the anti-apoptotic effect of ET-1 in hVECs. However, activation of ET receptor alone did not seem to contribute to the anti-apoptotic effect of ET-1. In addition, the anti-apoptotic effect of ETR was found to be associated with caspase 3 inhibition and does not depend on the density of this type of receptor. In conclusion, our results showed that ET-1 possesses an anti-apoptotic effect in hVECs and that this effect is mediated, to a great extent, via the activation of ETR. This study revealed a new role for ETR in the survival of hVECs.