This paper investigated the seismic retrofitting of an existing cable-stayed bridge through the use of a seismic isolation system. The bridge is situated in a high seismic zone. During the Saguenay earthquake 1988, one of the anchorage plates of the bridge supports failed. Herein, several configurations of seismic isolation system were considered to identify an appropriate solution for the seismic retrofitting of the bridge in both the longitudinal and transverse directions. A three-dimensional model of the bridge was created, and its seismic behavior studied through nonlinear dynamic time-history analysis. The comparative performance study among the five retrofitting configurations showed that the partial seismic isolation of the bridge led to an enhancement of the seismic response of the bridge in one direction only. However, the overall seismic response of the cable-stayed bridge substantially improved in the longitudinal and transverse directions in cases where the isolation systems were utilized between the supports and the deck-tower connection of the bridge.