Objectives The goal of this research was to determine the incremental cost and cost-effectiveness of embolic protection in patients undergoing percutaneous revascularization (PCI) of diseased saphenous vein bypass grafts (SVGs). Background Distal protection using the GuardWire balloon occlusion device has been shown to reduce major ischemic complications in patients undergoing SVG PCI, but the cost-effectiveness of this approach is unknown. Methods We prospectively measured medical resource utilization and cost for 801 patients undergoing SVG intervention who were randomized to distal protection using the GuardWire (n = 406) or conventional treatment (n = 395) in the Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial. Long-term survival and cost-effectiveness were projected based on observed 30-day outcomes and a validated survival model for postcoronary artery bypass graft patients. Results Compared with conventional treatment, distal protection increased initial procedural costs by ∼$1,600 ($6,326 vs. $4,779, p < 0.001). However, by reducing ischemic complications, distal protection reduced mean length of stay by 0.4 days and other hospital costs by nearly $1,000 ($6,846 vs. $7,811, p = 0.018). As a result, overall initial hospital costs were only $582 per patient higher with distal protection. Based on the observed 30-day cost and outcome differences in the trial, the incremental cost-effectiveness ratio for distal protection was $3,718 per year of life saved and remained <$40,000 per year of life saved in 97.3% of bootstrap simulations (95% confidence interval, $0 to $43,079). Conclusions For patients undergoing PCI of diseased SVGs, distal protection using the GuardWire system is an attractive use of limited health care resources.