This systematic review is the first update of a review published in 2013 and assesses the efficacy and safety of percutaneous transluminal angioplasty (PTA) with drug-eluting balloons (DEB) compared to PTA with uncoated balloons (UCB) for the treatment of peripheral artery disease (PAD) of various vascular regions. We only identified studies evaluating the intervention in patients with PAD of the lower extremities (femoropopliteal and infrapopliteal arteries). The available evidence indicates that PTA with DEB for patients with PAD (Rutherford category ≥3) in femoropopliteal arteries is more effective and not less safe than PTA with UCB. For infrapopliteal arteries, the available evidence is insufficient to assess the efficacy and safety of the intervention.