BACKGROUND: Increased concentrations of lipoprotein(a) [Lp(a)] have been considered a genetically determined risk factor for coronary artery and cerebrovascular disease. Only 2 small and conflicting studies have investigated the possibility of an association of peripheral arterial disease (PAD) with high serum Lp(a) concentrations and low molecular weight (LMW) phenotypes of apolipoprotein(a) [apo(a)]. METHODS: We measured serum concentrations of Lp(a) and apo(a) phenotypes in 213 patients with symptomatic PAD and 213 controls matched for sex, age (within 2 years), and presence of diabetes. RESULTS: Patients with PAD showed significantly higher median serum concentrations of Lp(a) (76 vs 47 mg/L; P = 0.003) and a higher frequency of LMW apo(a) phenotypes (41% vs 26%; P = 0.002) than controls. After adjustment for several potential confounders, increased Lp(a) concentrations (>195 mg/L, i.e., 75th percentile of the entire study sample) and LMW apo(a) phenotypes were significant predictors of PAD, with odds ratios of 3.73 (95% CI 2.08-6.67; P <0.001) and 2.21 (95% CI 1.33-3.67; P = 0.002), respectively. CONCLUSIONS: In this study sample, both increased serum concentrations of Lp(a) and the presence of LMW apo(a) phenotypes were associated with the presence of symptomatic PAD independent of traditional and nontraditional cardiovascular risk factors. Because PAD is considered an indicator of systemic atherosclerotic disease, our results suggest a possible role of Lp(a) as a genetically determined marker for systemic atherosclerosis.