PURPOSE We have previously shown that a program of upper limb exercise training can induce significant improvements in walking distance in patients with claudication. This study assessed whether upper limb exercise avoids the systemic inflammatory responses associated with lower limb exercise and also whether the inflammatory response to acute lower limb exertion is modified by a program of supervised exercise training. METHODS Fifty-two patients with stable intermittent claudication were randomized into two groups who underwent 6 weeks of supervised upper (n = 26) or lower (n = 26) limb cardiorespiratory exercise training. A parallel control group (n = 15) was provided with lifestyle advice only. Neutrophil activation markers (CD11b and CD66b) and plasma levels of von Willebrand factor (marker of endothelial damage) in response to an acute bout of sustained upper and lower limb exercise were assessed before and after the period of training. Plasma levels of soluble E-selectin (marker of endothelial activation) were also determined before and after the training period. RESULTS An acute bout of sustained lower limb exercise significantly increased the intensity of CD11b and CD66b expression by peripheral blood neutrophils in all groups, whereas upper limb exercise had no effect. Resting neutrophil expression of CD11b and CD66b and circulating von Willebrand factor levels were unaffected by the training program, as were the inflammatory responses to an acute bout of sustained upper and lower limb muscular work, despite the fact that both training programs significantly increased walking distances. CONCLUSIONS These findings indicate that upper limb exercise training programs may offer certain advantages over currently prescribed lower limb programs. Our results show that exercising nonischemic muscles in a way that promotes improved cardiorespiratory function and walking capacity can avoid the potentially deleterious systemic inflammatory responses associated with lower limb exertion in patients with stable intermittent claudication.