The independent associations of extreme temperature and ambient air pollutant with the admission to hospital and mortality of ischemic stroke have been widely investigated. However, knowledge about the modification effects of variation in season and temperature on the association between exposure to nitrogen dioxide (NO(2)) and ischemic stroke onset is still limited. This study purposed to explore the effect of NO(2) on daily ischemic stroke onset modified by season and ambient temperature, and identify the potential population that susceptible to ischemic stroke onset connected with NO(2) and ambient temperature. Data on daily ischemic stroke counts, weather conditions, and ambient air pollutant concentrations in Shenzhen were collected between January 1, 2008, and December 31, 2014. The seasonal effect on the NO(2)-associated onset was measured by a distributed-lag linear model. Furthermore, a generalized additive model that incorporated with stratification analyses was used to calculate the interactive effects between NO(2) and ambient temperature. During the winter, the average percentage increase in daily ischemic stroke onset for each 10 μg/m(3) increment in NO(2) concentration on lagged 2 days was 3.05% (95% CI: 1.31-4.82%), while there was no statistically significant effect of NO(2) during summer. And the low-temperature days ([Formula: see text] mean temperature), with a 2.23% increase in incidence (95% CI: 1.18-3.29%) for the same concentration increase in NO(2), were significant higher than high temperature days ([Formula: see text] mean temperature). The modification effects of temperature on the study association were more pronounced in individuals aged 65 years or more and in males. The adverse health effects of NO(2) on ischemic stroke are more pronounced during winter or low temperature periods. Elderly adults or males presented higher risks with these exposures.