Ventricular septal defect (VSD) is a severe complication of acute myocardial infarction and has a high mortality rate. This complication appears to have declined in the reperfusion era. It has mostly been reported in elderly or female patients who suffer from anterior wall infarction, patients with multivessel coronary artery disease (CAD) or occluded infarct-related artery (IRA) without collateral circulation, or patients who have had delayed reperfusion therapy. Here, we report the case of a 60-year-old male patient who presented with persistent chest pain and Killip I ST-segment-elevation myocardial infarction. Thrombolytic therapy was started 3 hours after the onset of chest pain. Based on the subsidence of chest pain, resolution of the elevated ST segment, and early peak of cardiac enzymes, reperfusion was thought to be successful. However, on the third day of admission, the patient complained of dyspnea after defecation and was found to have new-onset grade 3 pansystolic murmur over the left sternal border. Cardiac echography showed an apical VSD. A Swan-Ganz catheter was inserted into the right side of the heart; analysis of blood oxygen saturation revealed a 6% step-up of oxygen in the right ventricle. Coronary angiography showed only one-vessel CAD and TIMI 3 flow in the IRA. The patient received intensive medical management and underwent VSD repair and internal mammary artery bypass grafting to the left anterior descending artery. His recovery was uneventful. This case illustrates that VSD can be found in patients receiving early successful reperfusion therapy, with one-vessel CAD, and TIMI 3 flow in the IRA.