Percutaneous treatment of saphenous vein graft (SVG) lesions has been associated with higher rates of periprocedural complications and restenosis compared with non-SVG lesions. Whether these outcomes are similar in contemporary clinical practice, particularly when drug-eluting stents are used, is unknown. We evaluated outcomes of 110 consecutive patients who were treated with stent-assisted percutaneous coronary intervention for 145 SVG lesions (drug-eluting stents used in 91.0% of lesions). Embolic protection devices were used in 52.1% of treated grafts. Adverse events were recorded up to 1 year. Major or minor periprocedural myocardial necrosis occurred in 11 patients (10.9%). At 1-year clinical follow-up, we observed 13 myocardial infarctions (13.7%), 8 target lesion revascularizations (8.4%), 18 target vessel revascularizations (19.0%), 2 stent thromboses (2.1%), and 7 deaths (7.4%). The incidence of major adverse cardiac events, defined as death, myocardial infarction, or target vessel revascularization, was 30.5% at 1 year. By multivariable analysis, the presence of thrombus inside the graft before the procedure and the length of the stented segment were independent predictors of major adverse cardiac events at 1 year (hazard ratio for thrombus 4.07, 95% confidence interval 1.90 to 8.68, p = 0.0003; hazard ratio per millimeter of stented length 1.02, 95% confidence interval 1.01 to 1.03, p = 0.025). In conclusion, our data show that patients with SVG lesions remain a high-risk subgroup with worse outcomes after percutaneous coronary intervention compared with native vessel disease even in the era of drug-eluting stents.