The authors conducted a cross-sectional study of the association of serum selenium with the prevalence of peripheral arterial disease among 2,062 US men and women 40 years of age or older participating in the National Health and Nutrition Examination Survey, 2003-2004. Serum selenium was measured by using inductively coupled plasma-dynamic reaction cell-mass spectrometry. Peripheral arterial disease was defined as an ankle-brachial blood pressure index <0.90. The age-, sex-, and race-adjusted prevalence of peripheral arterial disease decreased with increasing serum selenium (P for linear trend = 0.02), but there was an indication of an upturn in risk in the highest quartile of serum selenium. The fully adjusted odds ratios for peripheral arterial disease comparing selenium quartiles 2, 3, and 4 with the lowest quartile were 0.75 (95% confidence interval: 0.37, 1.52), 0.58 (95% confidence interval: 0.28, 1.19), and 0.67 (95% confidence interval: 0.34, 1.31), respectively. In spline regression models, peripheral arterial disease prevalence decreased with increasing serum selenium levels up to 150-160 ng/mL, followed by a gradual increase at higher selenium levels. The association between serum selenium levels and the prevalence of peripheral arterial disease was not statistically significant, although a U-shaped relation was suggested.