Lower extremity peripheral artery disease occurs mostly in the elderly and is associated with high mortality. Limited data are available regarding long-term mortality in patients with premature lower extremity atherosclerosis (PLEA). Our objective was to determine the all-cause mortality and its predictors in younger PLEA patients.We studied patients with severe PLEA who were <55 years of age at diagnosis and treated at a single academic vascular center between 1998 and 2010. Data were collected prospectively at the initial evaluation for vascular care. National Death Index and hospital records were used to determine all-cause mortality. Demographic and clinical characteristics were summarized using count (%), mean (standard deviation), or median (interquartile range), and associations with aspirin use were tested using χ 2 test, t-test, or Wilcoxon test. Survival times were estimated using Kaplan-Meier estimates, and associations with covariates were tested using simple and multivariable Cox proportional hazards models.A total of 564 patients were analyzed (46% female; 20% nonwhite; mean age 49.4 [6.4] years). Ninety-five percent of patients had ≥2 cardiovascular risk factors, 31% had coronary artery disease (CAD), and 10% had a history of cancer. During median follow-up of 5.6 years (interquartile range, 2.3-8.3 years), 108 deaths (19%) were recorded. Two-year estimated mortality (standard error) was 6% (0.01), and 5-year estimated mortality was 16% (0.02). In univariate regression analysis, patient age (P = .04), prior amputation (P < .01), history of cancer (P = .03), and established CAD (P = .04) were associated with increased risk of mortality. Aspirin use and lipid-lowering therapy at the time of first evaluation were associated with improved survival (P < .01 and P = .02, respectively). A multivariable Cox proportional hazards model identified age (hazard ratio [HR] for 5-year increase, 1.17; 95% CI, 1.01-1.36; P = .04), prior amputation (HR, 1.99; 95% CI, 1.18-3.34; P = .01), history of cancer (HR, 2.35; 95% CI, 1.36-4.07; P < .01), and CAD (HR, 1.76; 95% CI, 1.16-2.67; P < .01) as independent predictors of mortality in patients with PLEA. Importantly, history of aspirin use had a significant protective effect (HR, 0.45; 95% CI, 0.30-0.69; P < .01). The impact of lipid-lowering therapy was no longer significant in multivariable modeling.Patients with PLEA demonstrate high all-cause mortality. No traditional cardiovascular risk factors predicted mortality. Aspirin therapy at the time of first evaluation was a significant and independent predictor of improved survival in patients with PLEA.