BACKGROUND: Endovascular procedures using a mobile C-arm are commonly performed in patients with peripheral artery disease. During these procedures, digital subtraction angiography (DSA) requires intra-arterial administration of contrast agent and exposes both patients and staff to radiation from the C-arm. The Vascular Navigation PAD system (Brainlab, Germany) may reduce the number of DSAs performed and thereby decrease both contrast agent use and radiation exposure. The objective of this study is to evaluate the safety and clinical performance of the Vascular Navigation PAD system compared with standard care in endovascular PAD treatment. The primary aim is to determine whether the device reduces the volume of contrast agent used during lower-extremity procedures. Secondary objectives include assessing patient and physician radiation exposure, patient air kerma, and the device's ability to support accurate endovascular navigation. METHODS: This is a multicenter, prospective, randomized confirmatory trial comparing navigation-assisted procedures with conventional procedures without navigation assistance. Patients allocated to the intervention group will undergo treatment using Vascular Navigation PAD in addition to a mobile C-arm. A total of 160 patients will be randomized in a 1:1 ratio, with 40 patients per group enrolled at each of the two participating hospitals. The primary endpoint is contrast agent volume. Secondary endpoints include patient radiation exposure, physician radiation exposure, fluoroscopy time, and the number of DSAs performed per intervention. DISCUSSION: This study will evaluate whether the Vascular Navigation PAD system can reduce the number of DSAs in endovascular treatment. A reduction in DSAs may lead to lower contrast agent use and reduced radiation exposure for both patients and staff. TRIAL REGISTRATION: The clinical trial is registered at the German Clinical Trials Register (ID: DRKS00035267). Registered on 10.Jan.2025.