Administration of fibrinolytic, antiplatelet, and antithrombotic agents by the intracoronary route may disaggregate clot, but the potential role of the mechanical force of the injection itself in decreasing clot burden has not been studied. Patients with ST-segment elevation myocardial infarction who were pretreated in the emergency room (ER) with unfractionated heparin and aspirin in the TITAN-TIMI 34 study were randomized to treatment with eptifibatide in the ER (n = 131) versus after diagnostic catheterization (n = 150). Quantitative coronary angiography was used to assess change in diameter stenosis from time of first contrast injection to injection before percutaneous coronary intervention (PCI) immediately preceding wire placement down the culprit artery in a matching view. Successful perfusion of the myocardium was assessed after PCI by the presence of Thrombolysis In Myocardial Infarction myocardial perfusion grade of 2 or 3. In patients treated with eptifibatide in the ER, there was a 1.3% absolute improvement in diameter stenosis from the first injection to the injection before PCI (p = 0.02), whereas there was no change in diameter stenosis in patients not treated with eptifibatide in the ER (0.0%, p = NS). Each 1% improvement in percent diameter stenosis during diagnostic injections before PCI was strongly correlated with an open muscle after PCI (adjusted odds ratio 1.09, 95% confidence interval 1.02 to 1.16, p = 0.012). In conclusion, the mechanical force of a contrast injection decreases thrombotic burden in patients with ST-segment elevation myocardial infarction pretreated with eptifibatide but not with placebo. Future trials of intracoronary pharmacotherapies should include a control arm in which saline is injected to account for the potential clot disaggregation that occurs as a result of iodinated contrast injections, particularly if the patient has been pretreated with aggressive pharmacotherapy.