In the single tower structure with large chassis, there will be seismic weak storey caused of the lateral stiffness mutation occurs at the connection between the large chassis and superstructure. In this paper, for an existing bottom frame-shear wall structure, the seismic isolation design was carried out, and the numerical models of its correspondent seismic structure, inter-storey isolation structure and base isolation structure were established by Structure Analysis Program 2000. The first three order natural vibration periods of the above three structures were calculated, and the interlaminar shear force, floor acceleration and storey drift of the above three structures under the action of fortification and rare earthquakes were compared to explore the best isolation scheme suitable for this kind of structure. The results of numerical simulation show that both inter-storey isolation system and base isolation system adopted on the single tower structure with large chassis can prolong its natural vibration periods obviously. Under the action of fortification earthquakes, the isolation effect of inter-storey isolation structure is superior to that of base isolation structure. Under the action of rare earthquakes, the storey drift cannot be controlled well for base isolation structure. However, the base isolation structure has a better weakening effect on the interlaminar shear force and floor acceleration than the inter-storey isolation structure, but its advantages are not significant. For the large chassis tower structure with lateral stiffness mutation, the isolation effect of the inter-storey isolation structure is better than that of the base isolation structure when considering fortification and rare earthquakes, and the inter-storey isolation structure is more economical concurrently due to the number of seismic isolators required is about half of that required for the base isolation structure.