BACKGROUND This study aimed to investigate intracoronary nicorandil treatment on the no-reflow phenomenon (NRP) during primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) and to compare nicorandil with sodium nitroprusside. MATERIAL AND METHODS Patients with sustained acute STEMI who underwent primary PCI (N=120) were randomly assigned to three groups: the nicorandil-treated group (N=40) had 2 mg of nicorandil injected into the coronary artery at 2 mm beyond the occlusion with balloon pre-dilation; the sodium nitroprusside-treated group (N=40) underwent the same procedure, but with 200 μg of sodium nitroprusside; the control group (N=40) received PCI and balloon pre-dilation only. Coronary angiography, incidence of NRP, hypotensive episodes, ST-segment resolution (STR) rate, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), wall motion score index (WMSI), and left ventricular ejection fraction (LVEF) were measured before and after primary PCI. Major adverse cardiovascular events (MACEs) post-PCI and at three-month follow-up were recorded. RESULTS Patients in the sodium nitroprusside and nicorandil groups had significantly improved thrombolysis in myocardial infarction (TIMI) scores, TIMI myocardial perfusion grade (TMPG), and ST-segment elevation resolution (STR) (P<0.05), and a significantly lower incidence of NRP (P=0.013). The incidence of intraoperative hypotension in the sodium nitroprusside group was significantly greater than the nicorandil and control groups (P=0.035). CONCLUSIONS Patients with sustained acute STEMI undergoing primary PCI, treated with intracoronary nicorandil had a reduced incidence of the NRP, improved myocardial perfusion and cardiac function.