OBJECTIVE This randomized controlled trial investigated the effects of upper- and lower-limb aerobic exercise training on disease-specific functional status and generic health-related quality of life (QOL) in patients with intermittent claudication. METHODS The study recruited 104 patients (mean age, 68 years; range, 50-85) from the Sheffield Vascular Institute. Patients were randomly allocated to groups that received upper-limb (ULG) or lower-limb (LLG) aerobic exercise training, or to a nonexercise control group. Exercise was performed twice weekly for 24 weeks at equivalent limb-specific relative exercise intensities. Main outcome measures were scores on the Walking Impairment Questionnaire (WIQ) for disease-specific functional status, the Medical Outcomes Study Short Form version 2 (SF-36v2), and European Quality of Life Visual Analog Scale (EQ-VAS) for health-related QOL. Outcomes were assessed at baseline, and at 6, 24, 48, and 72 weeks. RESULTS After 6 weeks, improvements in the perceived severity of claudication (P = .023) and stair climbing ability (P = .011) vs controls were observed in the ULG, and an improvement in the general health domain of the SF-36v2 vs controls was observed in the LLG (P = .010). After 24 weeks, all four WIQ domains were improved in the ULG vs controls (P ≤ .05), and three of the four WIQ domains were improved in the LLG (P <.05). After 24 to 72 weeks of follow-up, more consistent changes in generic health-related QOL domains were apparent in the ULG. CONCLUSIONS These findings support the use of alternative, relatively pain-free forms of exercise in the clinical management of patients with intermittent claudication.