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Several cohort studies have found associations between long-term exposure to air pollution and stroke risk. However, it is unclear whether the surrounding ecology may modify these associations. This study evaluates associations of air pollution with stroke risk by ecoregions, which are areas of similar type, quality, and quantity of environmental resources in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. We assessed the incidence of stroke in 26,792 participants (45+ yrs) from the REGARDS study, a prospective cohort recruited across the contiguous United States. One-yr and 3-yr means of PM 2.5 , PM 10 , O 3 , NO 2 , SO 2 , and CO were estimated at baseline using data from the Center for Air, Climate, & Energy Solution, and assigned to participants at the census block group level. Incident stroke was ascertained through September 30, 2020. Relations of air pollutants with the risk of incident stroke were estimated using Cox proportional hazards models, adjusting for relevant demographics, behavioral risk factors, and neighborhood urbanicity. Models were stratified by EPA designated ecoregions. A 5.4 μg/m3 (interquartile range) increase in 1-yr PM 10 was associated with a hazard ratio (95 %CI) for incident stroke of 1.07 (1.003, 1.15) in the overall study population. We did not find evidence of positive associations for PM 2.5 , O 3 , NO 2 , SO 2 , and CO in the fully adjusted models. In our ecoregion-specific analysis, associations of PM 2.5 with stroke were stronger in the Great Plains ecoregion (HR = 1.44) than other ecoregions, while associations for PM 10 were strongest in the Eastern Temperate Forests region (HR = 1.15). The associations between long-term exposure to air pollution and risk of stroke varied by ecoregion. Our results suggests that the type, quality, and quantity of the surrounding ecology can modify the effects of air pollution on risk of stroke. [Display omitted] • Long-term PM 10 concentrations were positively related to stroke risk. • PM effects were significantly modified by the ecological region of participants. • Associations of PM 2.5 on stroke were strongest in the Great Plains. • Urbanicity modified the relations between air pollution and stroke risk. [ABSTRACT FROM AUTHOR]