Contraction of muscle evokes the exercise pressor reflex (EPR), which is expressed partly by increases in heart rate and arterial pressure. Patients with peripheral artery disease (PAD) show an exaggerated EPR, sometimes report pain when walking and are at risk for cardiac arrthymias. Previous research suggested that reactive oxygen species (ROS) mediate the exaggerated EPR associated with PAD. To examine the effects of ROS on the EPR, we infused a superoxide scavenger, tiron, into the superficial epigastric artery of decerebrated rats. In some, we simulated PAD by ligating a femoral artery for 72 h before the experiment. The peak EPR in “ligated” rats during saline infusion averaged 31 ± 4 mmHg, whereas the peak EPR in these rats during tiron infusion averaged 13 ± 2 mmHg (n = 12; P < 0.001); the attenuating effect of tiron on the EPR was partly reversed when saline was reinfused into the superficial epigastric artery (21 ± 2; P < 0.01 vs tiron). The peak EPR in “ligated” rats was also attenuated (n = 7; P < 0.01) by infusion of gp91ds‐tat, a peptide which blocks the activity of NAD(P)H oxidase. Tiron infusion had no effect on the EPR in rats with patent femoral arteries (n = 9). Western blots showed that the triceps surae muscles of “ligated” rats expressed more Nox2 and p67phox, which are components of NADPH oxidase, than did triceps surae muscles of “freely perfused” rats. Tiron added to muscle homogenates reduced ROS production in vitro. Our results provide further evidence that ROS mediates the exaggeration of EPR in rats with simulated PAD. This article is protected by copyright. All rights reserved