Background: There are racial health disparities in many conditions for which oxidative stress is hypothesized to be a precursor. These include cardiovascular disease, diabetes, and premature aging. Small clinical studies suggest that psychological stress may increase oxidative stress. However, confirmation of this association in epidemiological studies has been limited by homogenous populations and unmeasured potential confounders. Purpose: We tested the cross-sectional association between self-reported racial discrimination and red blood cell (RBC) oxidative stress in a biracial, socioeconomically heterogeneous population with well-measured confounders. Methods: We performed a cross-sectional analysis of a consecutive series of 629 participants enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Conducted by the National Institute on Aging Intramural Research Program, HANDLS is a prospective epidemiological study of a socioeconomically diverse cohort of 3,721 Whites and African Americans aged 30-64 years. Racial discrimination was based on self-report. RBC oxidative stress was measured by fluorescent heme degradation products. Potential confounders were age, smoking status, obesity, and C-reactive protein. Results: Participants had a mean age of 49 years (SD = 9.27). In multivariable linear regression models, racial discrimination was significantly associated with RBC oxidative stress (Beta = 0.55, P < 0.05) after adjustment for age, smoking, C-reactive protein level, and obesity. When stratified by race, discrimination was not associated with RBC oxidative stress in Whites but was associated significantly for African Americans (Beta = 0.36, P < 0.05). Conclusions: These findings suggest that there may be identifiable cellular pathways by which racial discrimination amplifies cardiovascular and other age-related disease risks. © 2011 International Society of Behavioral Medicine.