We sought to determine, in United States (US) patients with the metabolic syndrome (MS), diabetes mellitus (DM), or preexisting cardiovascular disease, whether higher levels of C-reactive protein (CRP) would identify those with an increased likelihood of peripheral arterial disease (PAD). In a cross-sectional evaluation of the National Health and Nutrition Examination Survey (NHANES), 1999 to 2000, of 1,600 adults (representing a US population of 62.9 million) aged > or =40 years who had valid ankle-brachial index measurements available, subjects were categorized as having MS (without DM), DM, preexisting cardiovascular disease, or none of these conditions. The presence of PAD was defined as an ankle-brachial index <0.9. Subjects were also divided into groups according to CRP levels that were low (<1 mg/L), intermediate (1 to 3 mg/L), and elevated (>3.0 mg/L). Weighted multiple logistic regression analysis examined the odds of PAD by CRP group and disease category compared with the reference group of subjects who did not have MS, DM, or cardiovascular disease and had a CRP level of <1 mg/L. Those with MS (including DM) had an increased likelihood of PAD (odds ratio 4.8, 95% confidence interval 1.4 to 16.1, p = 0.01) as did those with MS without diabetes and an elevated CRP level (odds ratio 3.9, 95% confidence interval 1.1 to 14.6, p = 0.04); those with DM and an elevated CRP had the highest likelihood of PAD (odds ratio 8.6, 95% confidence interval 2.2 to 34.0, p = 0.001). In conclusion, the likelihood of PAD in US adults with MS and DM is enhanced by elevated CRP levels.