Background: Elevated plasma levels of Lp(a) lipoprotein have been linked to the development of premature atherosclerosis in the coronary circulation (coronary artery disease [CAD]). Although Lp(a) lipoprotein has been implicated as a risk factor for premature atherosclerosis in other locations, the patient populations described were not carefully screened for the coexistence of premature CAD. The purpose of this prospective study was to determine whether carefully screened patients with premature peripheral vascular disease (PVD) have elevated plasma levels of Lp(a) lipoprotein and to test the relative strength of Lp(a) lipoprotein level as a risk factor for premature PVD. Methods: We studied 55 consecutive white men with premature PVD (onset at 45 years of age or earlier) presenting to our vascular laboratory. Study subjects were substratified into 17 with PVD only and 38 with combined PVD and CAD (PVD+CAD). Two comparison groups included 26 age- matched white men with premature CAD recruited from the Cardiology Service after cardiac catheterization and 32 age-matched white male controls recruited from outpatient clinics. Results: Mean plasma apolipoprotein B-100 levels were higher in the CAD group than in controls (P=.013). Mean plasma Lp(a) lipoprotein levels were higher among the 17 patients with PVD only than among controls (P=.008). The covariance-adjusted mean Lp(a) lipoprotein levels were higher among all 55 patients with PVD than among controls (P=.014). Logistic regression analysis demonstrated two variables to be significantly related to premature PVD: Lp(a) lipoprotein level greater than 30 mg/dL (odds ratio, 3.9; 95% confidence interval, 1.1 to 13.7) and apolipoprotein B level greater than 95 mg/dL (odds ratio, 3.2; 95% confidence interval, 1.0 to 10.0). Conclusions: Lp(a) lipoprotein level is an independent, discriminating risk factor for premature PVD among white men.