Peripheral arterial disease (PAD) is an atherosclerotic obstructive disease of the arteries in lower extremities. Patients with PAD show high rates of mortality from coronary artery disease (CAD) and stroke. Smoking as well as diabetes is an important risk factor for PAD. A lesion of PAD in the lower extremities tends to be more proximal in smokers than in nonsmokers and to be more distal in patients with diabetes than in nondiabetics. By a systematic review, the odds ratio for PAD of smokers vs nonsmokers has been reported to be in the range of 1.7-7.4. Previous epidemiological studies suggest a stronger association of smoking with PAD than that with CAD. Nitric oxide (NO) is an important molecule suppressing the progression of atherosclerosis, but this function is compromised by smoking. Smoking decreases the bioactivity of NO and the expression level of NO synthase. In addition, smoking results in deteriorations of risk factors for atherosclerosis such as decreases in blood HDL (high-density lipoprotein) cholesterol and tissue plasminogen activator levels and increases in the levels of blood triglycerides, LDL (low-density lipoprotein) cholesterol, fibrinogen and the von Willebrand factor. Thus, smoking increases blood coagulability and deteriorates the blood lipid profile, resulting in thrombogenetic proneness and dyslipidemia. Smoking also increases the generation of atherogenic oxidized LDL in blood and decreases antiatherogenic prostacyclin production in the vascular endothelium. Smoking cessation is important for the prevention and therapy of PAD, and to this end, counseling by physicians and nicotine replacement therapy are useful and strongly recommended for patients with PAD.