BACKGROUND: Alkaline phosphatase (ALP) is elevated in peripheral arterial disease (PAD). We therefore examined the relationship of PAD with ALP and other liver enzymes in the United States National Health and Nutrition Examination Survey 1999-2004. METHODS: The analysis included 5995 men and non-pregnant women aged >or=40 years with no missing data in variables of interest. PAD was defined as ankle-brachial blood pressure index (ABI) <0.90 in either leg. RESULTS: Serum alkaline phosphatase (ALP) level was associated significantly with lower ABI after adjustment for confounding factors (p=0.019). No significant association of ABI with other liver enzymes was found. Serum ALP level increased with increasing age, body mass index, C-reactive protein, monocyte count, serum uric acid, lead, cadmium, and prevalence of hypercholesterolemia, diabetes, smoking, non-alcohol drinking, and cardiovascular diseases after adjusting for age, sex, race/ethnicity, and survey years (p<0.02). The highest quartile of serum ALP was associated with an odds ratio of 1.89 (95% confidence interval [CI]: 1.25-2.85) for PAD after adjustment for confounding factors (p for trend=0.023). In subjects with normal kidney function (glomerular filtration rate >90 ml/min/1.73 m(2)), the odds ratio increased to 4.22 (95% CI 1.45-12.35) (p=0.010). CONCLUSION: Elevated serum ALP is correlated with PAD, independent of other traditional cardiovascular risk factors.