Background: Cardiovascular disease is prevalent in first-degree relatives of young adults with premature-onset peripheral arterial occlusive disease (premature PAD), but it is not known whether the genetic influence is independent of other risk factors, the most prevalent of which is smoking. This study was performed to determine the relative contributions of family history and smoking to the development of occult PAD in siblings of patients with premature PAD. Methods: The prevalence of occult PAD was determined with carotid, abdominal, and lower extremity duplex ultrasound scanning in 50 asymptomatic siblings (25 men, 25 women) of patients with premature PAD (onset ≤49 years). Thirty of the siblings (60%) were active smokers, and 20 had never smoked. Age-matched and sex-matched reference groups included 50 asymptomatic heavy smokers (>20 cigarettes/day) and 50 nonsmokers. Results: Duplex ultrasound scans demonstrated raised arterial lesions in 20 asymptomatic siblings (40%), 20 heavy smokers (40%), and 2 nonsmoking control subjects (4%), resulting in 42 affected and 108 unaffected subjects. As expected, smokers were far more likely to have arterial lesions than were nonsmokers (odds ratio [OR], 11.19; 95% confidence interval [CI], 4.1-30.7; P < .0001). Individuals with a family history of premature PAD were almost three times more likely to have arterial lesions than those with no family history of cardiovascular disease (OR, 2.76; 95% CI, 1.3-5.8; P = .006). Stratified and multivariable logistic regression indicated no interaction between smoking and family history, indicating simple additive effects on PAD. Conclusions: Family history is a major determinant of occult PAD in young adults, and is at least as important as standard atherosclerotic risk factors. A high proportion of heavy smokers have clearly detectable lesions even though asymptomatic. Smoking and family history act additively to increase the risk for premature PAD.