Background: Numerous clinical conditions have been proposed to explain the premature onset of symptomatic peripheral vascular disease (PVD) in young adults, but the role of genetic factors has not been defined. This study was performed to determine the prevalence of cardiovascular disease among family members of patients with premature PVD. Methods: The prevalence of early cardiovascular events occurring in first-degree relatives of 90 subjects with premature PVD (onset ≤49 years) was determined. The prevalence of occult atherosclerosis was determined by duplex ultrasonography in a cohort of 20 asymptomatic siblings. Reference groups included first-degree relatives of 80 subjects with premature coronary artery disease (CAD) and first-degree relatives of 48 healthy subjects. Results: Cardiovascular events occurred at age 55 years or younger in 28% of the parents of PVD subjects, in 23% of parents of CAD subjects, and in 7% of the parents of healthy controls (P<.001). Cardiovascular events occurred in 24% of siblings of PVD subjects, in 14% of siblings of CAD subjects, and in 7% of siblings of healthy controls (P<.001). Duplex ultrasonography detected early plaques in the lower extremity circulation of 10 (50%) of the asymptomatic siblings of PVD subjects. Conclusions: Early, symptomatic cardiovascular disease is more common in first-degree relatives of individuals with premature PVD than in relatives of healthy individuals or of probands with premature CAD. Occult vascular disease in the lower extremity is prevalent among asymptomatic siblings of probands with premature PVD. These observations indicate that susceptibility to premature PVD has a familial basis.