A randomized placebo-controlled study was undertaken in 188 patients with severe intermittent claudication attending two vascular clinics in Manchester and Liverpool. After a 4-week run-in period, patients received active or placebo treatment for 24 weeks. Patients were assessed on a treadmill prior to the 4-week run-in period, at randomization, and at 8, 16, and 24 weeks. Outcome was measured in terms of change in pain-free walking distance, maximum walking distance, and pressure indices. In this severe claudication population, in which the patients presented with a mean pain-free walking distance of 60 m, an intention-to-treat analysis demonstrated that the outcome in the naftidrofuryl-treated group was significantly better than in the group receiving placebo (p = 0.045). Additionally, 7% of patients in the naftidrofuryl group deteriorated compared with 22% in the placebo group (p = 0.005). Of the various risk factors that were recorded during the study—smoking habits, the presence of hypertension, diabetes, obesity, and duration of illness—only duration of illness had a significant influence on outcome. Maximum walking distances alone were not significantly influenced by treatment, but the use of a combined index of pain-free walking distance, maximum walking distance, and pressure indices to record success or failure confirmed a significant treatment effect (p = 0.047). A higher incidence of minor gastrointestinal symptoms was recorded in the naftidrofuryl-treated group. Treatment with naftidrofuryl was shown to prevent or slow the deterioration observed in a group of patients with severe claudication over a 24-week period.