Background: Several studies indicate that lower extremity peripheral artery disease (PAD), commonly defined by an ankle-brachial index (ABI) <0.9, can increase the risk of bone fracture via its impact on physical function and mobility. Because the majority of prior studies are limited to older white male populations (age ≥65 years), uncertainty remains regarding this association in non-whites, women, and younger individuals. Methods: We studied 15,160 ARIC participants (age 45-64 years in 1987-1989) whose ABI was measured in a randomly selected leg at baseline. Hip or lower extremity fracture-related diagnostic codes were identified through active surveillance of hospitalizations. We used Cox proportional hazards to estimate the independent association between ABI including high ABI (≥1.4), a condition shown in PAD with vascular stiffness, and incident fracture hospitalization, adjusting for potential confounders. Results: There were 668 hip or lower extremity fracture hospitalizations during a median follow-up of 22 years. In the crude model, there was a dose-response relationship between low ABI and fracture risk (Table). However, only ABI 0.9-1.1 remained statistically significant after demographic adjustment compared to normal ABI (1.1-1.4) and inclusion of other covariates rendered this association non-significant. The results were largely consistent among most demographic and clinical subgroups, but we observed increased risk of fracture in low ABI (<0.9) among those with history of cardiovascular disease and high ABI (≥1.4) in men, in the fully adjusted model. Conclusion: An independent association of ABI with increased risk of hip or lower extremity fracture hospitalization was not that evident overall in our biracial population of middle-aged adults. However, ABI may contribute to increased risk of fracture in subgroups, warranting further investigation.