BACKGROUND The characterization of patients who have acute myocardial infarction (AMI) and insignificant coronary stenosis is unclear. OBJECTIVE The present study aimed to investigate the clinical profile, in-hospital and 3-month outcome of AMI patients with insignificant coronary stenosis in comparison with those with significant disease. METHODS This prospective observational study included 200 consecutive patients admitted with AMI. Group I (100 patients) included patients with insignificant CAD (all lesions <50% stenosis). Group II (100 patients) included patients with one or more lesions >70% stenosis. Patients with previous CABG were excluded. Patients with significant CAD had successful total revascularization. RESULTS Patients with insignificant CAD were significantly younger (61 vs. 67 years, p < 0.001), more likely to be females (41% vs. 23%, p = 0.006), less likely to smoke (p = 0.006), less likely to have diabetes mellitus (p < 0.001), and less likely to have history of CAD (p = 0.042) or prior PCI (p = 0.037). They were also less likely to have typical anginal pain at presentation (61% vs 91%, p < 0.001), less likely to have heart failure at presentation (9% vs 30%, p < 0.001), less likely to have ischemic ST-segment changes on presentation (10% vs 46%, p < 0.001), lower peak troponin (p < 0.001) and CK-MB levels (p < 0.001), with lower LDL-C (p = 0.006), and higher HDL-C level (p = 0.020). They were less likely to be treated with b-blockers (p = 0.002), ACEI/ARBS (p = 0.007), and higher rates of calcium channel blocker therapy (p < 0.001). They had lower prevalence of major adverse clinical events at follow-up (readmission for ACS (p = 0.009), need for revascularization (p = 0.035), recurrent chest pain (p = 0.009), and cardiogenic shock (p = 0.029). CONCLUSIONS Patients with AMI and insignificant CAD have different clinical profile and outcome compared to those with significant disease.