Rationale: Perceived discrimination adversely impacts individual and population health. However, limited studies have examined associations between discrimination and COVID-19 severity in a diverse cohort of adults. We investigated the association between lifetime discrimination and risk of severe COVID-19. Methods: This study included Black, Chinese, Hispanic, and White participants (45-84 years of age) from the Multi-Ethnic Study of Atherosclerosis (MESA). Lifetime discrimination (experiences of unfair treatment in 6 domains) was assessed at baseline (2000-2002). Incident COVID-19 was ascertained by the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) via questionnaires, serosurvey, and medical records in 2020-2023. Hospitalized and fatal cases were defined as severe; all other cases were defined as non-severe. Associations of lifetime discrimination and incident severe and non-severe COVID-19 were examined via Fine-Gray proportional sub-distribution hazards models, adjusting for covariates. Effect modification by sex, race/ethnicity, and educational attainment was tested. Results: Of 3,441 participants (mean age 76 years, 54% female, 13% Chinese, 20% Hispanic, 25% Black, 41% White), there were 248 cases of non-severe COVID-19 and 83 cases of severe COVID-19. Individuals reporting lifetime discrimination in ≥2 domains (vs none) had a two-fold higher hazard of severe COVID-19. Effect modification was observed by sex (P=.003) and educational attainment (P=.072), but not by race/ethnicity (P=.24). In stratified models, associations of lifetime discrimination and severe COVID-19 were stronger in women versus men and in participants with lower versus higher educational attainment ( Table ). Conclusion: Lifetime discrimination was associated with greater risk of severe COVID-19, particularly in women and persons with lower educational attainment. Further research is needed to understand mechanisms underlying these associations and to inform prevention and risk mitigation.