Abstract Aims Smoking, hypertension, hyperlipidemia, and diabetes are considered to increase the incidence of peripheral arterial disease (PAD). They can activate endogenous free radicals, cause inflammation and oxidative stress, and lead to endothelial cell dysfunction. Hydrogen (H2) has been proven to decrease oxidative stress, improve cell function, and reduce chronic inflammation. The purpose of this research was to validate the role of H2 in individuals who are at risk of PAD.Methods Sixty subjects were randomly assigned to placebo (PBO) group or H2-rich water (HRW) group and drank either bottled pure water or H2-rich water (245 mL/time, 3 times/d) for ten weeks.Results The pulse wave velocity was ameliorated in the HRW group with no significant change in the ankle-brachial index. The serum total cholesterol of the HRW group was significantly reduced compared to the placebo group. In addition, compared to baseline, the levels of lipoprotein(a) was decreased, the malondialdehyde content was reduced, the superoxide dismutase activity was increased, and the expression of intercellular cell adhesion molecule-1 was decreased significantly in the HRW group. The oxidized phospholipid of 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphatidylcholine level in the HRW group were significantly reduced compared to the placebo group. Finally, H2 significantly improved the antioxidant, antiinflammatory, and antiapoptotic abilities of high-density lipoprotein (HDL).Conclusions Drinking HRW can improve vascular sclerosis indicators, improve dyslipidemia, reduce vascular oxidative stress and inflammation, and improve HDL function. H2 may be used to prevent and relieve PAD caused by major risk factors such as smoking, hypertension, hyperlipidemia, and diabetes.