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. cardiovascular disease; discrimination; race/ethnicity; risk factors Abbreviations: CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; MESA, Multi-Ethnic Study of Atherosclerosis.Racial/ethnic disparities in cardiovascular disease (CVD) risk in the United States are well-documented (1) but not clearly understood. Experiences of ethnic discrimination and racism have long been considered to contribute to racial/ethnic disparities in CVD rates (2), but evidence for this is scarce. As several reviews have highlighted (3-6), much of the extant literature on perceived discrimination and racism has focused on mental health consequences; more recently, studies have linked discrimination to physical health outcomes, including several indicators of cardiovascular health and functioning, such as higher prevalence of carotid artery atherosclerosis and coronary artery calcification, higher blood pressure, greater visceral fat and central adiposity, and higher levels of C-reactive protein and E-selectin (7-16).Evidence linking discrimination to CVD risk factors is inconsistent, with positive, null, and conditional associations that vary by race/ethnicity and/or sex being observed (see Lewis et al. (2) and Williams et al. (17) for reviews). Moreover, there is debate in the literature as to whether racial/ ethnic discrimination is more deleterious to health than other forms of discrimination (18). Few studies examining discrimination and CVD risk factors...