Background: Approximately 8.5 million Americans are affected by lower extremity PAD, which is associated with a substantially greater risk of cardiovascular (CV) events, mortality and functional decline. In 2010, the AHA initiated new CV health metrics (Life’s Simple 7) to monitor the goal of significantly improving CV health by the year 2020. The extent to which Life’s Simple 7 may be associated with risk of PAD or change in the ankle brachial index (ABI), the major clinical diagnostic criterion for PAD, has not been established. Methods: MESA is a population-based prospective cohort of 6814 Caucasian, African-American, Hispanic and Chinese men and women from six US field centers. The baseline exam occurred in 2000-02. Life’s Simple 7 at baseline included AHA definitions of poor, intermediate and ideal health behaviors (diet, body mass index, smoking, physical activity) and health factors (blood pressure, glucose, cholesterol), and was modeled continuously on a 0-14 point scale, with a higher score indicating better CV health. The scale was also categorized into overall inadequate (0-7points), average (8-11) and optimum (12-14) CV health. Incident PAD was defined as an ABI≤0.90 at Exam 3 (2004-05) or Exam 5 (2010-12), removing participants both with ABI>1.40 and prevalent PAD at baseline. Cox models were used for incident PAD analyses and change in the ABI over time was assessed using mixed models. All models were adjusted for age, sex and race/ethnicity. Results: The mean±SD Life’s Simple 7 score was 8.4±2.1, with 33.8% of participants classified as inadequate, 59.6% average, and 6.6% classified as having optimum CV health. Adjusted rates of PAD per 1000 person-years were 7.3 for inadequate, 3.2 for average and 1.1 for optimum CV health. Each point higher on the Life’s Simple 7 scale was associated with a 20% lower risk of incident PAD (95% CI (0.76-0.85); p<0.001). Compared to inadequate CV health, participants with average and optimum health had a 55% lower risk (95% CI (0.37-0.56), p<0.001) and an 85% lower risk (95% CI (0.06-0.38); p<0.001) of incident PAD, respectively. Each point higher on the scale was associated with a higher average ABI over a median follow-up time of 9.4 years (0.006 (95% CI (0.005, 0.007), p<0.001). Compared to those with inadequate health, participants with average and optimum health maintained a 0.021 (95% CI (0.016, 0.027, p<0.001) and a 0.030 (95% CI (0.018, 0.041, p<0.001) greater average ABI over the follow-up period, respectively. Conclusions: Maintaining average or optimum CV health results in a substantially reduced risk of incident PAD and also in maintaining a higher average ABI over time, even when accounting for age, sex and race/ethnicity. Encouraging improvement in health behaviors, and treatment to achieve and maintain better levels of CV health metrics, may contribute to decreasing the rate of PAD.