Exercise is associated with a rise in heart rate, blood pressure (BP) and blood flow to active skeletal muscle that is mediated by the exercise pressor reflex and modified by regional release of vasodilator factors. In peripheral artery disease (PAD) the exercise pressor reflex is enhanced and the ability to raise blood flow to the affected limb is impaired. To assess the functional impact of the enhanced exercise pressor reflex on regional blood flow in limbs affected by PAD, we determined beat-by-beat BP and mean blood velocity (MBV, Doppler) in the popliteal artery, and calculated vascular conductance index (VC, MBV/mean BP) in the exercising (ipsilateral) or contralateral resting leg during graded rhythmic plantar flexion exercise in 7 patients with symptomatic PAD (age 67±2 yrs, body-mass-index 27.9±1.1) and in 5 healthy age-matched controls (2 exercise trials with each leg). At peak exercise (2.0 kg, 1 contraction/sec), the pressor effect was greatest in PAD when exercise was performed with the “ischemic” leg (ankle-brachial index 0.58±0.05; mean ΔBP +9.1±2.0 mmHg), lower with the less affected leg (ankle brachial index 0.76±0.07; mean ΔBP +6.9±1.6 mmHg) and lowest in the controls (ankle brachial index 1.11±0.04; mean ΔBP +3.9±1.8 mmHg). In controls, VC increased in the exercising leg ( P <0.05) but did not change in the inactive contralateral leg ( P =NS). Similarly, in PAD, VC increased in the exercising “ischemic” leg ( P <0.05) but did not change in the inactive contralateral leg ( P =NS). In sharp contrast, while VC increased in the less affected exercising leg ( P <0.05), in the contralateral resting “ischemic” leg VC decreased by 24±10% ( P <0.05). Similarly, when static handgrip at 30% maximum voluntary contraction to fatigue served as the exercise stimulus, vasoconstriction was noted in the “ischemic” leg (n=5; P <0.05). Thus, unlike in the exercising leg, in the resting “ischemic” leg activation of the exercise pressor reflex resulted in substantial vasoconstriction. This suggests that despite activation of peripheral vasodilator mechanisms downstream to the arterial obstruction, the vasculature of the “ischemic” leg is exquisitely sensitive to reflex vasoconstriction.