We sought to determine the influence of vessel diameter on the efficacy of distal protection devices during saphenous vein graft intervention. From the Filterwire EX Randomized Evaluation trial, in which patients who underwent saphenous vein graft stenting were randomized to distal protection with the GuardWire or FilterWire EX, outcomes in 572 patients were examined in vessel size tertiles. The 30-day composite incidence of major adverse cardiac events (MACEs) increased with vessel size and was 6.9%, 9.7%, and 14.9% in the smallest, middle, and largest tertiles, respectively (p = 0.04). MACE rates were relatively vessel size independent for the GuardWire but increased steadily with vessel size with the FilterWire EX. In the smallest tertile, MACEs were reduced by 71% with the FilterWire EX compared with the GuardWire (p = 0.05), with the devices showing similar event rates in the other tertiles.