Purpose: An improvement of the methodology used for the implementation of the first industrial symbiosis platform in Italy is proposed aimed at solving some critical issues encountered during its application at a regional scale in Sicily. Methods: The investigation mainly focused on the phases of companies’ involvement and operative meeting organization. The different sectors characterizing the companies participating in the meetings were analyzed and compared with the productive system features in the investigated area. Resources shared by the companies during the operative meeting and the individuated potential matches were analyzed, as well. Results: Several critical issues were identified: (a) the low grade of diversification of participating companies that was not fully representative of the actual productive system so limiting the information on the potential matches; (b) the disequilibrium between observed supply and demand due to the prevalent interest of participating companies in finding out alternative solutions for the disposal of their residues rather than to find alternative supplies for their processes; (c) the excessive offers of services and expertise; (d) companies concern about a potential increase in controls on their activities. Conclusions: Solutions were proposed to increase the “biodiversity” of the firms, the level of companies knowledge on the potential for substituting their input resources, the control of “alien” species and to promote greater confidence in the symbiosis approach between the companies, as well as a greater awareness between the same stockholders. Finally the encouragement of paths that are not so financially attractive but that can have a strong positive impact on the environment is proposed.