For researching the isolation distance of landfill with virus as isolation target, a modeling method based on system health risk objective was proposed to determine the influence of groundwater gradient, hydraulic conductivity and aeration zone thickness on isolation distance. Based on linear dose-effect model and acceptable infection risk [<10^-4/(person·a)], the concentration limit of enterovirus in drinking water was deduced. An analytical model of pollutant leakage-migration-degradation was constructed by coupling the leakage source strength model with the vertical migration and transformation model of water flow and virus in the aeration zone and the horizontal migration and transformation model in the aquifer. The uncertainty of parameters in the analytical model was characterized by Monte-Carlo simulation, and then a typical domestic waste landfill site was selected for case study. The result indicated that the isolation distance in sand aquifer is 44~564m, in gravel aquifer was 91m~2.39km and in coarse gravel aquifer was 1.74~27.29km. Groundwater gradient changed from 0.001 to 0.05, resulting in the isolation distance at the highest gradient was 10~20 times larger than that at the lowest gradient. When the thickness of aeration zone increases from 1 to 10m, the isolation distance could be shortened to less than 10m. The research indicated that the determination of isolation distance should be based on specific safety requirements and hydrogeological conditions.