BACKGROUND: Both genetic factors and environmental air pollution contribute to the risk of stroke. However, it is unknown whether the association between air pollution and stroke risk is influenced by the genetic susceptibilities of stroke and its risk factors. METHODS: This prospective cohort study included 40 827 Chinese adults without stroke history. Satellite-based monthly fine particulate matter (PM _2.5 ) estimation at 1-km resolution was used for exposure assessment. Based on 534 identified genetic variants from genome-wide association studies in East Asians, we constructed 6 polygenic risk scores for stroke and its risk factors, including atrial fibrillation, blood pressure, type 2 diabetes, body mass index, and triglyceride. The Cox proportional hazards model was applied to evaluate the hazard ratios and 95% CIs for the associations of PM _2.5 and polygenic risk score with incident stroke and the potential effect modifications. RESULTS: Over a median follow-up of 12.06 years, 3147 incident stroke cases were documented. Compared with the lowest quartile of PM _2.5 exposure, the hazard ratio (95% CI) for stroke in the highest quartile group was 2.72 (2.42–3.06). Among individuals at high genetic risk, the relative risk of stroke was 57% (1.57; 1.40–1.76) higher than those at low genetic risk. Although no statistically significant interaction was found, participants with both the highest PM _2.5 and high genetic risk showed the highest risk of stroke, with ≈4× that of the lowest PM _2.5 and low genetic risk group (hazard ratio, 3.55 [95% CI, 2.84–4.44]). Similar upward gradients were observed in the risk of stroke when assessing the joint effects of PM _2.5 and genetic risks of blood pressure, type 2 diabetes, body mass index, atrial fibrillation, and triglyceride. CONCLUSIONS: Long-term exposure to PM _2.5 was associated with a higher risk of incident stroke across different genetic susceptibilities. Our findings highlighted the great importance of comprehensive assessment of air pollution and genetic risk in the prevention of stroke.