Background: This paper introduces a proof-of-concept trial in progress, supposedly providing new important information on anti-platelet drugs used in patients with peripheral arterial disease (PAD). The Arteriogenesis Competence Network (Art.Net.) of the Universities of Basel, Berlin, and Freiburg could show in animal models that Aspirin (ASA), in contrast to Clopidogrel, inhibits the formation of an appropriate collateral network (arteriogenesis). This trial is supposed to reproduce the animal data in man. Materials and methods: In a prospective, double-blind, parallel-group, bi-national (D, CH), multicentre trial, 250 patients will be randomised to either 100 mg ASA or 75 mg Clopidogrel once daily. Patients will then enter a three months structured rehabilitation programme with daily physical training supposed to induce arteriogenesis. The claudication distances will be tested as the primary endpoint at baseline, 6 weeks, and at 3 months. Also, the 24h physical activity profile of all patients will be electronically documented. Conclusions: This trial will provide information on potential disadvantages when using ASA in PAD patients. If data emerging from animal pharmacology can be reproduced in man, the present standard scheme of anti-aggregant treatment in PAD patients has to be reconsidered.