We intended to investigate the combined effect of smoking and hypertension on ischemic stroke incidence based on a 10-year prospective study among Inner Mongolians in China. A prospective cohort study from June 2003 to July 2012 was conducted among 2589 participants aged 20 years and older from Inner Mongolia, China. We categorized the participants into 4 subgroups according to the status of smoking and hypertension. The cumulative incidence rates of ischemic stroke among the 4 subgroups were estimated using Kaplan-Meier curves and compared by log-rank test. Cox proportional hazard model was used to compute hazard ratios of ischemic stroke across the 4 subgroups after adjusting for important confounding factors. The cumulative incidence rates of ischemic stroke were .85%, 2.05%, 3.19%, and 8.14% among non-hypertension/non-smokers, non-hypertension/smokers, hypertension/non-smokers, and hypertension/smokers, respectively. The multivariable-adjusted hazard ratios [95% confidence intervals] of ischemic stroke for hypertension and smoking were 1.84 [1.05-3.23] and 1.89 [1.11-3.22], respectively. The hazard ratios [95% confidence intervals] of ischemic stroke for non-hypertension/smokers, hypertension/non-smokers, and hypertension/smokers were 1.37 [.56-3.33], 1.34 [.54-3.29], and 2.93 [1.26-6.83], respectively, compared with the non-hypertension/non-smokers. Significant interaction was detected between smoking and hypertension on the risk of ischemic stroke. Our study indicated that participants with coexistence of smoking and hypertension were at the highest risk for ischemic stroke. There was a significant interaction between smoking and hypertension on the risk of ischemic stroke.