Purpose. A systematic methodology for industrial symbiosis development at a regional scale is presented. The methodology was applied for the first time in Sicily as a pilot project with the aim of promoting productive development in southern Italy. Methods. A platform is projected as an instrument to enable the transfer of resources and offer other services including a legal database, LCA and ecodesign tools and best practices guidelines specifically addressed to SMEs. Promotions activities and local stakeholders involvement were carried out during all the project duration. A database containing information on more than 2000 enterprises was firstly developed for group of heterogeneous companies selection in order to represent the most important productive sectors. Then operative meetings were organized for selected enterprises involvement in sharing information about resources fluxes and wastes and looking for potential synergies. Results. During the meetings more than 80 SME were linked giving rise to almost 240 output resources and almost 190 input resources. More than 650 potential matches were found between the participating enterprises showing interesting opportunities both for substituting resources with waste products in real and virtual cases and for sharing waste management services and infrastructures. Conclusions. The discussion occurred during the meeting has highlighted the significance and the consequences of the regulatory and control system on IS application, underlining the necessary participation of local stakeholders and control authorities and the needs of identify predominant productive activities in well-defined territorial contexts where to investigate the specific/local tangles involving legislative and technical-economic feasibility. Results also show that the used methodology for industrial symbiosis development is suitable for further implementations in other regions.