Perceived discrimination is positively related to cardiovascular disease (CVD) risk factors; its relationship with incident CVD is unknown. Using data from the Multi-Ethnic Study of Atherosclerosis, a population-based multiethnic cohort study of 6,508 adults aged 45-84 years who were initially free of clinical CVD, we examined lifetime discrimination (experiences of unfair treatment in 6 life domains) and everyday discrimination (frequency of day-to-day occurrences of perceived unfair treatment) in relation to incident CVD. During a median 10.1 years of follow-up (2000-2011), 604 incident events occurred. Persons reporting lifetime discrimination in ≥2 domains (versus none) had increased CVD risk, after adjustment for race/ethnicity and sociodemographic factors, behaviors, and traditional CVD risk factors (hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.09, 1.70) and after control for chronic stress and depressive symptoms (HR = 1.28, 95% CI: 1.01, 1.60). Reported discrimination in 1 domain was unrelated to CVD (HR = 1.05, 95% CI: 0.86, 1.30). There were no differences by race/ethnicity, age, or sex. In contrast, everyday discrimination interacted with sex (P = 0.03). Stratified models showed increased risk only among men (for each 1-standard deviation increase in score, adjusted HR = 1.14, 95% CI: 1.03, 1.27); controlling for chronic stress and depressive symptoms slightly reduced this association (HR = 1.11, 95% CI: 0.99, 1.25). This study suggests that perceived discrimination is adversely related to CVD risk in middle-aged and older adults.