We have previously shown oxidative damage and edema within skeletal muscle following contractile-induced claudication. To investigate the sources of this oxidative damage in the gastrocnemius muscle, we administered allopurinol (to inhibit xanthine oxidase) and cyclophosphamide (to deplete neutrophils), prior to inducing contractile claudication in male Sprague Dawley rats. Contractile-induced claudication (LS) caused a significant increase in xanthine oxidase activity (SS = 2.57 ± 0.07; LS = 3.22 ± 0.07) and neutrophil infiltration (SS = 0.47 ± 0.03; LS = 0.91 ± 0.10) compared to controls (SS), and this was associated with increased lipid peroxidation, protein oxidation, muscle damage, and edema. Pretreatment with allopurinol (ALLO) attenuated the increase in xanthine oxidase activity and attenuated lipid hydroperoxides (control LS = 12.85 ± 0.50; ALLO LS = 9.96 ± 0.71), muscle damage, and neutrophil infiltration (control LS = 0.91 ±0.10; ALLO LS = 0.61 ± 0.07). This latter finding suggests that xanthine oxidase-derived oxidants are chemotactic to neutrophils. Pretreatment with cyclophosphamide (CYCLO) reduced neutrophil infiltration (control LS = 0.91 ± 0.10; CYCLO LS = 0.55 ± 0.02) and attenuated lipid peroxidation (control LS = 12.85 ± 0.50; CYCLO LS = 6.462 ± 0.62), protein oxidation (control LS = 2.59 ± 0.47; CYCLO LS = 1.77 ± 0.60), muscle damage, and edema. Together, these data indicate that contractile claudication causes an increase in xanthine oxidase activity and neutrophils in muscle and that inhibition of these oxidant sources protects against oxidative stress, muscle damage, and edema.