The efficacy and safety of high-dose nicorandil therapy in acute myocardial infarction (AMI) have not yet been clarified. This is a prospective study including 30 patients who received nicorandil at 0.06 mg/kg/h [standard dose nicorandil (SDN) group] and 32 patients who received a bolus injection of nicorandil 0.2 mg/kg followed by a continuous infusion at 0.2 mg/kg/h [high-dose nicorandil (HDN) group]. The benefits and adverse events were assessed during acute phase and 12-month follow-up period. There were no significant differences between the groups in blood pressure, heart rate or urine volume 2, 6 and 24 h after drug administration, although blood pressure decreased during acute phase. The percentages of patients who required dose reduction or discontinuation of nicorandil were 34.4 and 16.7 % in HDN and SDN groups, respectively (p = 0.11). In HDN group, subgroup analysis revealed that the TIMI frame count (TFC) was significantly lower in patients in whom the treatment was started within 12 h compared to those more than 12 h (17.0 vs. 21.0, p = 0.017) and in patients with baseline WBC elevation compared to those without it (16.5 vs. 22.0, p = 0.029). A TFC of >20 was significantly associated with being in HDN group [odds ratio (OR) 0.27; 95 % confidence interval, CI 0.07-0.89], onset-to-balloon time (OR 1.06; 95 % CI 1.01-1.16), and ∑creatine kinase (OR 7.27; 95 % CI 1.40-57.83). There were no significant differences in incidences of cardiovascular death, rehospitalization, and target lesion revascularization between the groups. HDN therapy may improve coronary microcirculation in patients with AMI.