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Purpose To identify randomized controlled trials that compared antiplatelet monotherapy to combination antiplatelet plus anticoagulant therapy and evaluated major adverse cardiovascular events (MACE) or major adverse limb events (MALE), death, or bleeding in patients with lower extremity peripheral artery disease (PAD). Summary A systematic search of MEDLINE, Embase, and CENTRAL databases revealed 5 trials. Two trials consisted of patients with stable PAD, while 3 trials examined patients with PAD post revascularization. Antiplatelet therapy was mostly aspirin (81-325 mg daily), and anticoagulation included rivaroxaban 2.5 mg twice daily or warfarin. Duration of follow-up ranged from 12 to 38 months. Two trials had low risk of bias, whereas 3 trials had high/unclear risk of bias. For patients with stable PAD, one trial showed that use of warfarin (or acenocoumarol) with antiplatelet therapy did not reduce MACE, MALE, or cardiovascular or all-cause death but increased the risk of life-threatening bleeding. A second trial demonstrated that low-dose rivaroxaban plus antiplatelet therapy lowered the risk of MACE and MALE, with no effect in preventing cardiovascular or all-cause death, but increased the risk of major bleeding. For patients with PAD post revascularization receiving warfarin and antiplatelet therapy, 2 trials showed no benefit in MACE or MALE but increased or similar rates of all-cause death and major bleeding. In a third trial, low-dose rivaroxaban plus aspirin reduced occurrence of the composite of MACE and MALE but increased major bleeding, with no effect on cardiovascular or all-cause death. Conclusion Dual-pathway inhibition with low-dose rivaroxaban and aspirin reduced MACE and MALE in patients with stable or revascularized PAD, but net clinical benefit is questionable.