Spontaneous ST-segment resolution (STR) after acute ST-elevation myocardial infarction is associated with favorable outcomes. Effect on STR of newer, more powerful antiplatelet and antithrombotic agents is unclear. The aim of this study was to identify independent clinical and angiographic predictors of STR in patients with ST-elevation acute myocardial infarction before percutaneous coronary intervention. We studied 206 patients admitted with ST-elevation acute myocardial infarction, of whom 37 (18%) had STR. There were 12 deaths (5.8%) that occurred in the group without spontaneous STR. Patients with spontaneous STR were younger (55 vs 61 years old, p = 0.02), had shorter duration of symptoms (117 vs 212 minutes, p <0.0001), had preserved ejection fraction (55% vs 40%, p <0.0001), had shorter hospital stays, and had lower in-hospital arrhythmias or death. Independent predictors of STR, identified by stepwise logistic regression analysis, were early clopidogrel administration (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.00 to 4.40, p = 0.045), single-vessel disease (OR 2.85, 95% CI 1.22 to 6.70, p = 0.02), chest pain duration (OR 0.98, 95% CI 0.98 to 0.99, p <0.0001), collaterals (OR 4.3, 95% CI 1.7 to 10.8, p = 0.002), circumflex as a culprit vessel (OR 4.74, 95% CI 1.5 to 14.95, p = 0.008), and coronary thrombus noted on angiography (OR 5.76, 95% CI 1.63 to 20.4, p = 0.006). In conclusion, early clopidogrel administration is associated with, and likely causal for, STR. Patients with thrombus, collateral flow, and circumflex culprit vessel are more likely to have STR. In addition, our study confirms previous findings that patients with STR have preserved left ventricular function and better hospital outcomes compared with those without STR.