DESYRE (DEcision Support sYstem for the REqualification of contaminated sites) is a GIS-based decision support system (DSS) specifically developed to address the integrated management and remediation of contaminated megasites (i.e., large contaminated areas or impacted areas characterized by multiple site owners and multiple stakeholders). In the DESYRE conceptual design and development the main aspects pertaining to a remediation process—analysis of social and economic benefits and constrains, site characterization, risk assessment, selection of best available technologies, creation of sets of technologies to be applied, analysis of the residual risk, and comparison of different remediation scenarios—were included. The DESYRE DSS is a GIS-based software composed of 6 interconnected modules. In the characterization module, chemical and hydrogeological data are organized in a relational database and contaminants' distributions are mapped by using geostatistic tools. The socioeconomic module addresses the socioeconomic constraints though a fuzzy logic analysis to select the best land use. The risk assessment module is divided into 2 phases. In the preremediation phase, an original procedure allows assessing and representing the spatial distribution of risks posed by contaminants in soil and groundwater, providing a risk-based zoning of the site. Then, in the technology assessment module, a selection of suitable technologies and creation of different technology sets, taking into account both technical requirements and site-specific features, are performed by experts supported by multicriteria decision analysis tools. In the postremediation risk assessment, a simulation of applied technologies provides residual risk maps with related uncertainty maps. Finally, in the decision module, alternative remediation scenarios are described by a set of indices and can be compared and ranked by interested stakeholders using multicriteria decision analysis methodologies. The paper highlights original procedural steps and functionalities of DESYRE and analyzes its main points of strength and potentialities, as well as limits.