Background <p>Ethnic disparities in ischemic stroke are substantial and differences in exposure to air pollution have been demonstrated as well. However, the role of air pollution in mediating ethnic disparities in risk of ischemic stroke remains unclear. Understanding this relationship is crucial, as air pollution is a major modifiable risk factor for ischemic stroke. This study aims to determine whether air pollution exposure mediates ischemic stroke risk differences between Indonesian, Surinamese, Dutch Caribbean, and ethnic Dutch populations.</p> Methods <p>We carried out a nationwide cohort study in the Netherlands (2014–2019), including 9,248,484 residents aged 30 or older, free of ischemic stroke at baseline, of Dutch, Surinamese, Indonesian, or Dutch Caribbean ethnicity. Ethnicity was defined based on the country of birth of the individual and their parents. Air pollution exposure was measured via annual residential estimates of particulate matter &lt; 2.5 micrometers (PM_2.5) and nitrogen dioxide (NO₂) for 2014. The study outcome was time to ischemic stroke occurrence or mortality, identified from nationwide hospital discharge and death registries using ICD-9/ICD-10 codes.</p> Results <p>The cohort included 314,082 (3.4%) Indonesian, 204,158 (2.2%) Surinamese, 69,580 (0.8%) Dutch Caribbean and 8,660,664 (93.7%) ethnic Dutch individuals. Air pollution levels were highest among Surinamese and lowest among Dutch. For Surinamese, NO₂ mediated 13.8% (11.0-17.5%) and PM_2.5 mediated 7.9% (6.3–9.9%) of the ischemic stroke difference compared to ethnic Dutch. For Dutch Caribbeans, NO₂ mediated 14.7% (9.8–26.7%) and PM_2.5 mediated 8.0% (8.1–23.3%). Percentages could not be calculated for Indonesians.</p> Conclusion <p>Air pollution substantially mediates the increased ischemic stroke risk in Surinamese and Dutch Caribbean populations. These findings emphasize the urgent need for air pollution reduction strategies to mitigate the disproportionate ischemic stroke burden in these populations.</p>