This study states that Available paclitaxel (PTX) drug-coated balloons (DCBs) employ different PTX composition, dose, and excipient. DCBs decrease restenosis compared with uncoated balloons (plain old balloon angioplasty [POBA]), but they have not been compared with each other. Our aim was to compare outcome in patients treated with two discrete DCBs. We performed a retrospective review of 1357 consecutive patients who underwent femoropopliteal artery intervention by angioplasty, atherectomy, stent placement, or combination between 2011 and 2019. Patients were divided by balloon: POBA; Admiral IN.PACT (IPA; PTX, 3.5 μg/mm2; excipient, urea; Medtronic, Minneapolis, Minn); or Lutonix (LTX; PTX, 2.0 μg/mm2; excipient, polysorbate and sorbitol; Bard, Tempe, Ariz). Survival, amputation-free survival (AFS), freedom from major amputation (FF-Amp), and freedom from target vessel revascularization (FF-TVR) were compared using Kaplan-Meier analysis. Individual DCBs may not yield equivalent outcomes. Through 4-year follow-up, IPA showed a clear advantage in revascularization of the femoropopliteal segment over POBA. LTX had a less clear advantage. Further studies are needed to determine the ideal PTX compositions, dose, and excipient.