Activation of melatonin receptors protects the heart against ischemia-reperfusion injury. Ramelteon, a clinically used drug for insomnia, acts via activation of melatonin receptors. We investigated whether ramelteon induces acute infarct size reduction by postconditioning. Male Wistar rats were randomized to 6 groups. Hearts were treated with melatonin and ramelteon at the beginning of reperfusion. The melatonin receptor inhibitor luzindole was administered with and without melatonin and ramelteon, respectively. Ramelteon reduced infarct size to the same extent as melatonin. Both effects were completely abolished by luzindole. The results show for the first time that ramelteon induces cardioprotection by postconditioning.