Background: Randomized clinical trials comparing glycoprotein IIb-IIIa inhibitors have largely excluded patients with ST segment elevation myocardial infarction (STEMI). Methods: We conducted an open-label, sequential comparison of inhospital and 6-month clinical outcomes in STEMI patients receiving eptifibatide or abciximab as adjunctive therapy during percutaneous coronary intervention (PCI). Registry data were collected and compared for STEMI patients undergoing PCI and receiving eptifibatide or abciximab over a 3.5-year period. Six-month follow-up, using telephone interviews, included major adverse cardiac events and functional status. Results: Baseline characteristics were similar for patients receiving eptifibatide (n = 294) or abciximab (n = 158). No significant differences in hospital clinical outcomes were observed for reinfarction (2 vs. 3% for eptifibatide and abciximab, respectively), repeat revascularization (3 vs. 4%), bleeding complications (8 vs. 12%), congestive heart failure (5 vs. 3%), cerebrovascular accidents (0 vs. 2%), renal failure (2 vs. 3%), and all-cause mortality at discharge (5 vs. 4%). No significant difference was seen between groups in all-cause mortality at 6 months (6.5 vs. 6.4%; hazard ratio 0.976; 95% confidence interval 0.43–2.23; log-rank, p = 0.95). Conclusions: No significant differences were observed in clinical outcomes between STEMI patients receiving eptifibatide or abciximab in the setting of PCI. Considering the substantially lower cost of eptifibatide, these data suggest that eptifibatide can be substituted for abciximab to lower overall medication costs while maintaining beneficial safety and efficacy effects.