Muscle metabolic by-products during exercise such as K⁺, lactic acid, ATP, H⁺ and phosphate are well established to be involved in the reflex cardiovascular response to static muscle contraction. However, the role of muscle reactive oxygen species (ROS), a metabolic by-product during muscle contraction, in the exercise pressor reflex (EPR) has not been investigated in detail. In the present study, we evaluated the role of muscle ROS in the EPR in a decerebrate rat model. We hypothesized that muscle NADPH Oxidase ROS contributes to sensitization of the EPR. Thus the rise in blood pressure and heart rate in response to a 30-second static contraction induced by electrical stimulation of L4/L5 ventral roots were compared before and after hindlimb arterial infusion of the redox agents: diethyldithiocarbamate (DETC) a superoxide dismutase (SOD) inhibitor, the SOD mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine 1-oxyl (Tempol), the free radical scavenger dimethylthiourea (DMTU), a NADPH oxidase inhibitor, Apocynin and a xanthine oxidase inhibitor, Allopurinol. The EPR-induced pressor response was augmented after treatment with DETC and was attenuated after treatment with Tempol, DMTU and Apocynin. Treatment with Allopurinol did not affect the EPR function. None of the drug's effected the EPR heart rate response. In addition, neither the pressor response to electrical stimulation of the central end of dorsal roots nor femoral blood flow was affected by any treatment. These data suggest that NADPH oxidase-derived muscle ROS plays an excitatory role in the EPR control of blood pressure.