The relation between inflammation and peripheral arterial disease (PAD) is not well characterized. This study examined this relation and its consistency across important subgroups in a cross-sectional, nationally representative sample of the adult United States population. C-reactive protein (CRP), fibrinogen, leukocyte count, and PAD were assessed in a sample of 4,787 participants aged>or=40 years in the National Health and Nutrition Examination Survey 1999-2002. PAD was defined as an ankle-brachial blood pressure index <0.9. Graded relations were present between inflammatory markers and PAD. The multivariate adjusted odds ratios of PAD associated with the highest versus the lowest quartile of CRP, fibrinogen, and leukocyte count were 2.14 (95% confidence interval [CI] 1.41 to 3.25), 2.49 (95% CI 1.27 to 4.85), and 1.67 (95% CI 0.84 to 3.31), respectively (each p trend<0.05 across quartiles). Associations between inflammation and PAD were similar across gender, obesity, and diabetic subgroups. However, the odds ratios of PAD for the highest CRP quartile versus the 3 lowest quartiles were 3.10 (95% CI 1.76 to 5.45) for non-Hispanic blacks versus 1.50 (95% CI 0.98 to 2.28) for non-Hispanic whites and 1.11 (95% CI 0.57 to 2.17) for Mexican Americans (p interaction=0.049) and 5.59 (95% CI 1.82 to 17.17) for patients aged 40 to 54 years versus 2.01 (95% CI 1.13 to 3.58) for patients aged 55 to 69 years and 0.98 (95% CI 0.65 to 1.48) for patients aged>or=70 years (p interaction=0.018). Odds ratios of PAD for the highest fibrinogen quartile versus the lowest 3 quartiles were 3.26 (95% CI 1.69 to 6.28) for current smokers versus 0.83 (95% CI 0.51 to 1.35) for never smokers (p interaction=0.006). In conclusion, in the general United States adult population, inflammation is independently associated with PAD.