Background: Cardiovascular disease (CVD) is the leading cause of death in the US accounting for the highest death rates found in Blacks and Whites. Human paraoxonase (PON1, PON2, PON3) enzymes have antioxidant properties inhibiting the formation and accumulation of cholesterol. Major adverse cardiac events (MACE) is a composite cardiovascular outcome comprised of first occurrence of pre-specified cardiac events. Ankle-brachial index (ABI) is the ratio of systolic blood pressures of the lower extremity divided by the upper extremity. Peripheral arterial disease (PAD) is diagnosed as ABI <0.9. Objectives were to evaluate the association of race with 1) MACE 2) PAD and 3) change in ABI over time and effect modification of PON SNPs on these associations. Methods: Data analyzed came from the Atherosclerosis Risk in Communities (ARIC) Study, a large population-based prospective cohort conducted at 4 field-centers across the US. Participants 45-64 years, Black or White race, enrolled in 1987 with four follow-up visits. Analysis was limited to 12,711 participants with genotype data. Results: After adjusting for age, gender, BMI, cigarette and alcohol use, educational and marital status and reported aspirin use, Blacks had 1.24 times greater hazard of MACE compared to Whites, which became non-significant after adjusting for comorbidities. After adjusting for age, BMI, and gender, Blacks had 1.27 higher odds of PAD than Whites, but differences became non-significant after adjustment for smoking, education and comorbidities. After adjusting for confounders, Whites had significantly higher (better) ABI values than Blacks at both follow-up visits. When stratified by education, ABI over time was better in both Blacks and Whites who completed high school than those with less education. Due to the lack of main effect of PON SNPs, there was no effect modification found on these associations. Conclusions: Modifiable health and behavioral risk factors and comorbidities may be major determinants of MACE and PAD. ABI differences by race were statistically significant but small and may not be clinically significant. Higher education may influence health management contributing to better ABI in Blacks and Whites. No effect modification was found on these associations due to the lack of main effect of the PON SNPs.