Distal embolization during percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) lesions is associated with a high risk of myonecrosis and myocardial infarction. PCI guidelines advocate the use of distal embolic protection devices, when technically feasible, in patients undergoing PCI for SVG disease. To date, alternative management strategies are not fully investigated. We report a case of an 84-year-old male patient with acute coronary syndrome who underwent PCI for a quite occlusive stenosis of an SVG on the first diagonal branch of the left anterior descending artery complicated by wide endoluminal thrombosis with poor antegrade coronary blood flow and absent opacity of the distal first diagonal vessel. A strategy of delayed PCI after upstream, 48 h long tirofiban administration in order to obtain a thrombus burden reduction was decided. After tirofiban administration, a high-level thrombus resolution was obtained, with a significant improvement in coronary flow, and a successful PCI with stenting was performed. There was neither clinical nor instrumental periprocedural sign of ischemia, and the patient remained asymptomatic throughout his hospital stay. Preprocedural tirofiban administration followed by PCI with stenting of an SVG thrombotic lesion without a distal protection device might be a well-tolerated and feasible option for patients with degenerated SVG disease. Further studies are needed to further expand our findings.