Background—Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD).

Methods and Results—We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [0.85 to 0.96]) compared with women (OR 0.97 [0.91 to 1.04]; P_interaction=0.05), and was stronger among active smokers (OR 0.81 [0.73 to 0.90]) compared with nonsmokers (OR 0.97 [0.93 to 1.02]; P_interaction<0.01).

Conclusions—Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.