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 US, we identified a cohort with high-risk conditions for cardiovascular and thromboembolic events (CTE) and linked individuals with seasonal average zip code level concentrations of fine particulate matter (PM2.5). We assessed the relationship between seasonal PM2.5 exposure and hospitalization for each of seven CTE-related causes using history-adjusted marginal structural models adjusted for individual demographic and neighborhood socio-economic variables as well as baseline comorbidities, 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, 60% female, 87% white). A 1 μg/m3 increase in PM2.5 exposure was significantly associated with increased risk of six out of seven CTE hospitalization types. Strong increases were observed for transient ischemic attack (HR: 1.039 (1.034,1.044)), venous thromboembolism (HR: 1.031 (1.027,1.035)), and heart failure (HR: 1.019 (1.017,1.020)). Asian Americans were found to be particularly susceptible to thromboembolic effects of PM2.5 (venous thromboembolism HR: 1.063 (1.021,1.106)), while Native Americans were most vulnerable to cerebrovascular effects (transient ischemic attack HR: 1.093 (1.030,1.161)).