Lipoprotein (a) [Lp(a)] is a serum protein that has been reported to be predictive of complications from coronary and cerebrovascular atherosclerotic disease. This study was designed to compare plasma levels of Lp(a) in 100 white male patients with and without peripheral vascular disease (PVD) and to determine the role of Lp(a) as a risk factor for PVD independent of known risk factors such as cigarette smoking (CIG), diabetes mellitus (DM), and coronary artery disease (CAD). Patients with PVD (mean age = 67.6 years, n = 50) had a statistically significant (p = 0.04) elevation of Lp(a) (29.8 +/- 3.9 mg/dl) as compared to patients without PVD (20.0 +/- 2.9 mg/dl (mean age = 68.3 years, n = 50). Further analysis revealed that patients with PVD had a significantly higher incidence of CIG (86% vs. 68%, p = 0.03), DM (34% vs. 14%, p = 0.02), and CAD (52% vs. 30%, p = 0.02) than those without PVD. However, there was no statistically significant difference in Lp(a) levels in patients with CIG or CAD compared to those without. Patients with DM had significantly (p = 0.04) lower levels of Lp(a) (17.8 +/- 3.5 mg/dl) than those without DM (27.1 +/- 3.0 mg/dl). Stepwise regression analysis of these various risk factors for PVD revealed that Lp(a) was the strongest significant individual predictor for the presence of PVD (R2 = 0.07) as compared to DM (R2 = 0.05) and CIG (R2 = 0.04). We conclude that there is a significant correlation of Lp(a) levels and the incidence of PVD, which is independent of other major risk factors for PVD.