ABSTRACT: BACKGROUND:Stroke, especially ischemic stroke (IS), has been a severe public health problem around the world. However, the association between air pollution and ischemic stroke remains ambiguous. METHODS:A total of 63, 997 IS cases aged 18?years or above in Shenzhen were collected from 2008 to 2014. We used the time-stratified case-crossover design combining with distributed lag nonlinear model (DLNM) to estimate the association between air pollution and IS onset. Furthermore, this study explored the variability across gender and age groups. RESULTS:The cumulative exposure-response curves were J-shaped for SO2, NO2 and PM10, and V-shaped for O3, and crossed over the relative risk (RR) of one. The 99th, 50th (median) and 1st percentiles of concentration (?g/m3) respectively were 37.86, 10.06, 3.71 for SO2, 116.26, 41.29, 18.51 for NO2, 145.94, 48.29, 16.14 for PM10, and 111.57, 49.82, 16.00 for O3. Extreme high-SO2, high-NO2, high-PM10, high-O3, and low-O3 concentration increased the risk of IS, with the maximum RR values and 95% CIs: 1.50(1.22, 1.84) (99th vs median) at 0-12 lag days, 1.37(1.13, 1.67) (99th vs median) at 0-10 lag days, 1.26(1.04, 1.53) (99th vs median) at 0-12 lag days, 1.25(1.04, 1.49) (99th vs median) at 0-14 lag days, and 1.29(1.03, 1.61) (1st vs median) at 0-14 lag days, respectively. The statistically significant minimal RR value and 95% CI was 0.79(0.66,0.94) at 0-10 lag days for extreme low-PM10. The elderly aged over 65?years were susceptible to extreme pollution conditions. Difference from the vulnerability of males to extreme high-SO2, high-NO2 and low-O3, females were vulnerable to extreme high-PM10 and high-O3. Comparing with the elderly, adults aged 18-64?year were immune to extreme low-NO2 and low-PM10. However, no association between CO and IS onset was found. CONCLUSIONS:SO2, NO2, PM10 and O3 exerted non-linear and delayed influence on IS, and such influence varied with gender and age. These findings may have significant public health implications for the prevention of IS.