In the Western world, cardiovascular disease is still the most common cause of death. Over the past decade it has become clear that apart from common risk factors, high concentrations of total homocysteine are relavant to the process of atherosclerosis, especially in the development of premature vascular disease. Hyperhomocysteinaemia (HHC) can be found in 25-32% of the patients with premature peripheral arterial occlusive disease (PAD). Retrospective and prospective studies, evaluating the clinical course of patients with PAD, showed significant associations between high concentrations of total homocysteine and the severity of atherosclerosis and with a more rapid disease progression and mortality rates. HHC can be treated with vitamin B6 and folic acid. Although there may be indications that there is a protective effect of treatment, prospective randomized clinical trials are urgently needed to unravel the role of HHC and its treatment in patients with premature PAD.