Background Meta-analyses have shown that isometric handgrip training (IHT) can reduce brachial systolic and diastolic blood pressure (BP) by >6/4 mm Hg, respectively. However, whether IHT promotes these effects among patients with peripheral artery disease, who exhibit severe impairment in cardiovascular function, is currently unknown. This study aimed to evaluate the effects of IHT on the cardiovascular function of patients with peripheral artery disease. Methods and Results A randomized controlled trial with peripheral artery disease patients assigned to either the IHT or control group was conducted. The IHT group performed 3 sessions per week, for 8 weeks, of unilateral handgrip exercises, consisting of 4 sets of isometric contractions for 2 minutes at 30% of maximum voluntary contraction and a 4-minute interval between sets. The control group received a compression ball in order to minimize the placebo effects, representing sham training. The primary outcome was brachial BP. The secondary outcomes were central BP, arterial stiffness parameters, cardiac autonomic modulation, and vascular function. The IHT program reduced diastolic BP (75  mm Hg preintervention versus 72  mm Hg postintervention), with no change in the control group (74  mm Hg preintervention versus 74  mm Hg postintervention), with this between-group difference being significant (P=0.04). Flow-mediated dilation improved in the IHT group (6.0% [5.7] preintervention versus 9.7% [5.5] postintervention), with no change in the control group (7.6% [5.5] preintervention versus 7.4% [5.1] postintervention), with this between-group difference being significant (P=0.04). There was no change in other measured variables over the intervention period. Conclusions IHT reduced brachial diastolic BP and improved local vascular function in patients with peripheral artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02742220.