BACKGROUND: Although the association of short-term ozone and heatwave exposure with cerebrovascular disease has been well documented, it remains largely unknown whether their co-exposure could synergistically trigger ischemic stroke (IS) mortality. METHODS: We performed an individual-level, time-stratified case-crossover analysis utilizing province-wide IS deaths (n = 59079) in warm seasons (May-September) during 2016-2019, across Jiangsu, eastern China. Heatwave was defined according to a combination of multiple temperature thresholds (90-97.5th percentiles) and durations (2-4 days). Daily estimates of ozone concentration (0.01° × 0.01°) and heatwave (0.1° × 0.1°) were extracted from spatiotemporal grid dataset at subject's residential address. Conditional logistic regression models were utilized to evaluate the associations of short-term ozone and heatwave exposure with IS mortality. Multiplicative and additive interaction effects of ozone and heatwave were assessed using stratified analyses via dividing cases into low and high exposure groups. RESULTS: Ozone exposure was associated with an increased odds of IS mortality, exhibiting an approximately linear trend across the broad concentration range of 59-227 μg/m CONCLUSIONS: Compound ozone and heatwave exposure may synergistically trigger IS deaths, and old adults were at higher vulnerability to exposure-related excess risk. Coordinated governance of climate change and air pollution may potentially bring substantial cerebrovascular health benefit.