Background: Whether low molecular weight heparin (LMWH) is superior or similar to unfractionated heparin (UFH) in the setting of off-label use of drug-eluting stents (DES) in acute ST-segment elevation myocardial infarction (STEMI) is unclear. Methods: A total of 2,575 STEMI patients (pts) undergoing primary percutaneous coronary intervention (PCI) with DES received LMWH (n=1,229 pts, subcutaneous LMWH bid for 5-7 days), or UFH (n=1,342 pts, a bolus of intravenous UFH 5,000 U, followed by 24,000 U/day infusion for at least 48 hours). The in-hospital complications and clinical outcomes at 7 days and 1 month were evaluated. Results: Compared with UFH, LMWH significantly and independently associated with lower incidences of cardiac death [multivariate odd ratio (OR) 0.53, 95% confidence interval (CI) 0.34 to 0.81, P=0.004], total death (multivariate OR 0.45, 95% CI 0.30 to 0.69, P<0.001), coronary artery bypass graft (multivariate OR 0.27, 95% CI 0.08 to 0.97, P=0.045) and total major adverse cardiac events (MACE, multivariate OR 0.59, 95% CI 0.42 to 0.83, P=0.002) at 1 month. However, the incidences of recurrent myocardial infarction and Repeat PCI were similar between the two groups. Interestingly, the incidence of ischemic cerebrovascular accidents (CVA) was significantly lower in LMWH group (0.4% vs. 1.0%, P=0.045), but the incidences of major and minor bleeding were similar between the two groups. Conclusions: LMWH usage in acute STEMI was associated with lower mortality, MACE and CVA compared with UFH. LMWH appears to be superior to UFH in acute STEMI pts undergoing PCI with DES.