Platelet glycoprotein (GP) IIb/IIIa inhibitors are widely used in percutaneous coronary intervention (PCI). Previous studies have suggested that they do not offer benefit in saphenous vein graft PCI. Nonetheless, their use remains widespread during vein graft angioplasty. We retrospectively analyzed 1,537 patients who underwent saphenous vein graft PCI. Patients who received a GP IIb/IIIa inhibitor (n = 941) were compared with those who did not receive any GP IIb/IIIa inhibitor (n = 596). The primary end point was myonecrosis after PCI (creatine kinase-MB level >3 times the upper reference limit). The incidence of myonecrosis after PCI was similar between the group that received GP IIb/IIIa and the group that did not (odds ratio for GP IIb/IIIa use 1.39, 95% confidence interval 0.97 to 2.00, p = 0.07). Propensity-adjusted analysis demonstrated no significant difference in myonecrosis after PCI, in-hospital mortality, Q-wave myocardial infarction, or bleeding (blood transfusion, retroperitoneal bleed, or hematoma) between the 2 groups. In an analysis restricted to patients who were treated with an emboli protection device, GP IIb/IIIa use was not associated with decreased myonecrosis after PCI (this was also the case for patients who were not treated with an emboli protection device). Unadjusted survival (mean follow-up 5.5 ± 0.1 years) was similar between the group that received GP IIb/IIIa and the group that did not (log-rank test, p = 0.89). There was no difference in survival after adjusting for the propensity to receive a GP IIb/IIIa inhibitor (adjusted odds ratio for GP IIb/IIIa use 0.92, 95% confidence interval 0.69 to 1.23, p = 0.59). In conclusion, adjunctive use of platelet GP IIb/IIIa inhibitors in saphenous vein graft PCI does not appear to be associated with less myonecrosis or improved survival.