Peripheral vascular disease is characterized by progressive atherosclerotic deterioration of peripheral arteries and coronary and cerebral vascular complications. Antiplatelet treatment retards the progression of peripheral atherosclerosis but it is still unclear if this is associated with a reduced risk of amputation. Vasodilator prostaglandins have been administered in critical ischemia but the results have been disappointing. An alternative approach to enhance peripheral vasodilation is to increase nitric oxide production, which is reduced in peripheral vascular disease, particularly in the case of severe ischemia. Critical ischemia secondary to thromboembolism has been treated with thrombolysis within 7 days of the acute episode, but this approach is no more effective than vascular surgery in reducing amputation; earlier treatment should be planned to further investigate its clinical efficacy. The effect of antiplatelet treatment in preventing cardiovascular events was investigated in three randomized trials with negative results. A post-hoc analysis of the CAPRIE study demonstrated that clopidogrel is superior to aspirin in preventing cardiovascular disease. This suggests that antiplatelet treatment may be efficacious in this setting; future study should assess if its combination with other drugs, such as statins, that retard coronary atherosclerotic progression, could further reduce cardiovascular complications in peripheral vascular disease.