Seismic rehabilitation of structural systems is an effective approach for reducing potential seismic losses such as social and economic losses. However, little or no effort has been made to develop a framework for making decisions on seismic rehabilitation of structural systems that systematically incorporates conflicting multiple criteria and uncertainties inherent in the seismic hazard and in the systems themselves. This study develops a decision support framework for seismic rehabilitation of structural systems incorporating uncertainties inherent in both the system and the seismic hazard, and demonstrates its application with detailed examples. The decision support framework developed utilizes the HAZUS method for a quick and extensive estimation of seismic losses associated with structural systems. The decision support framework allows consideration of multiple decision attributes associated with seismic losses, and multiple alternative seismic rehabilitation schemes represented by the objective performance level. Three multi-criteria decision models (MCDM) that are known to be effective for decision problems under uncertainty are employed and their applicability for decision analyses in seismic rehabilitation is investigated. These models are Equivalent Cost Analysis (ECA), Multi-Attribute Utility Theory (MAUT), and Joint Probability Decision Making (JPDM). Guidelines for selection of a MCDM that is appropriate for a given decision problem are provided to establish a flexible decision support system. The resulting decision support framework is applied to a test bed system that consists of six hospitals located in the Memphis, Tennessee, area to demonstrate its capabilities.