Little epidemiologic research has focused on pollution-related risks in medically vulnerable or marginalized groups. Using a nationwide 50% random sample of 2008–2016 Medicare Part D–eligible fee-for-service participants in the United States, we identified a cohort with high-risk conditions for cardiovascular and thromboembolic events (CTEs) and linked individuals with seasonal average zip-code–level concentrations of fine particulate matter (particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM_2.5)). We assessed the relationship between seasonal PM_2.5 exposure and hospitalization for each of 7 CTE-related causes using history-adjusted marginal structural models with adjustment for individual demographic and neighborhood socioeconomic variables, as well as baseline comorbidity, health behaviors, and health-service measures. We examined effect modification across geographically and demographically defined subgroups. The cohort included 1,934,453 individuals with high-risk conditions (mean age = 77 years; 60% female, 87% White). A 1-μg/m³ increase in PM_2.5 exposure was significantly associated with increased risk of 6 out of 7 types of CTE hospitalization. Strong increases were observed for transient ischemic attack (hazard ratio (HR) = 1.039, 95% confidence interval (CI): 1.034, 1.044), venous thromboembolism (HR = 1.031, 95% CI: 1.027, 1.035), and heart failure (HR = 1.019, 95% CI: 1.017, 1.020). Asian Americans were found to be particularly susceptible to thromboembolic effects of PM_2.5 (venous thromboembolism: HR = 1.063, 95% CI: 1.021, 1.106), while Native Americans were most vulnerable to cerebrovascular effects (transient ischemic attack: HR = 1.093, 95% CI: 1.030, 1.161).