Objective: The onset of symptomatic peripheral arterial disease at a young age (premature PAD) has been associated with rapid progression, bypass graft failure, and amputation. This study was performed to document the incidence of these complications and to determine the risk factors for poor outcome in patients with premature PAD. Methods: This study was designed as a prospective longitudinal analysis, with patients who were ambulatory or hospitalized at a single vascular referral institution. The subjects were 51 white men with onset of PAD symptoms before the age of 45 years (mean age of onset, 41 ± 0.5 years) and represented consecutive patients who were seen at the vascular surgery service during a 4-year period. Thirty of the study subjects (58%) were recruited during the first 2 years. The main outcome measures were number and type of lower extremity revascularization procedures or amputations that were necessitated during the follow-up period. Results: During a mean follow-up period of 73 ± 6 months, 15 patients (29%) had PAD that remained stable without interventions and 15 (29%) had PAD that remained stable for a mean of 76 ± 13 months after a single intervention. Twenty-one patients (41%) required multiple operations or major amputations. In a comparison of the 30 PAD patients whose conditions were stable with or without a single intervention with the 21 PAD patients who required multiple interventions (REDO), there were no differences in smoking, hypertension, diabetes, or dyslipidemias. The REDO group had a younger mean age at the onset of symptoms (39 ± 1 years vs 43 ± 2 years; P< .001). At entry, the REDO patients had a higher prevalence of infrainguinal or multilevel disease (57% vs 20%; P = .03), a lower mean ankle brachial index (0.44 ± 0.04 vs 0.56 ± 0.03; P = .02), and more frequent tissue loss (24% vs 0; P = .005). The REDO patients had a higher mean lipoprotein (a) level than did the patients with stable conditions (51 ± 11 mg/dL vs 27 ± 5 mg/dL; P = .03), but there were no significant differences in the mean plasma homocysteine levels (19 ± 2 μmol/L vs 16 ± 1 μmol/L) or in the proportion of patients with hypercoagulable states (33% vs 30%). The only predictive variables that were selected with stepwise logistic regression analysis were age at onset (P < .002; odds ratio, 1.4; 95% confidence interval, 1.11 to 1.81) and ankle brachial index of less than 0.5 (P < .008; odds ratio, 6.4; 95% confidence interval, 1.5 to 27.3). Conclusion: Although 60% of the white men with premature PAD who were referred to a vascular surgery service had conditions that appeared to remain stable, these data show that approximately 40% of the patients will require multiple interventions because of disease progression or bypass graft failure. Clinical indicators, not serum markers, are predictors of poor outcome in patients with premature PAD. The results of this study suggest that patients with onset of PAD before the age of 43 years who have objective evidence of advanced disease are predisposed to multiple interventions.