Abstract This study examines the safety and efficacy of low molecular weight heparin (LMWH) in combination with platelet glycoprotein (GP) IIb/IIIa inhibitors in patients with acute myocardial infarction (AMI). LMWH has been shown to be as effective as unfractionated heparin (UFH) in the treatment of acute coronary syndrome (ACS), but there are limited data regarding the safety and efficacy of LMWH in combination with GP IIb/IIIa inhibitors. We studied 37,320 patients in the National Registry of Myocardial Infarction 3 who were treated with GP IIb/IIIa receptor antagonists from April 1998 to September 2000. Using univariate analysis, clinical events were compared between 2,482 patients who received LMWH and 34,838 patients who were treated with UFH. To adjust for confounding covariates, a multivariate regression analysis was also performed. Major bleeding rates were 4.0% in patients on LMWH versus 4.2% in patients who were treated with UFH (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.80 to 1.23, p = 0.92). Similarly, there was no significant difference in the occurrence of recurrent myocardial ischemia (OR 0.93, 95% CI 0.82 to 1.06, p = 0.26), and in-hospital death (OR 0.86, 95% CI 0.71 to 1.05, p = 0.14) between groups. There was a trend toward a decreased risk of recurrent AMI in patients who received LMWH compared with those on UFH (1.5% vs 1.9%, OR 0.74, 95% CI 0.53 to 1.05, p = 0.09). LMWH appears to be a safe and effective alternative to UFH in patients with AMI who receive IIb/IIIa inhibitors.