Published reports have indicated that prodromal angina before acute myocardial infarction (AMI) is associated with better outcomes and that nicorandil has cardioprotective effects on ischemic hearts. We compared cardioprotective effects of intravenous nicorandil with preconditioning effects by prodromal angina in patients with AMI who underwent percutaneous coronary intervention (PCI). In total, 368 patients with first ST-elevation AMI who underwent PCI were randomly assigned to receive nicorandil 12 mg or a placebo intravenously just before PCI. Subjects were assigned to 1 of 4 groups: 52 patients with prodromal angina were given placebo, 129 patients without prodromal angina were given nicorandil, 56 patients with prodromal angina were given nicorandil, and 131 patients without prodromal angina were given placebo. Coronary microvascular impairment after PCI was prevented at similar frequencies in groups with prodromal angina and groups on nicorandil. Five-year rates for freedom from major cardiac events were similar across groups with prodromal angina given placebo, without prodromal angina given nicorandil, and with prodromal angina given nicorandil (92.3%, 93.8%, and 92.9%, respectively) but were significantly lower in the group without prodromal angina given placebo (80.2%, p = 0.0019, 0.044, and 0.042, respectively). In conclusion, intravenous administration of nicorandil before PCI exerts pharmacologic cardioprotective effects similar to ischemic preconditioning in patients with AMI.