Interoperability testing is widely recognized as a key to achieve seamless interoperability of smart grid applications, given the complex nature of modern power systems. In this work, the interoperability testing methodology proposed by the European Commission Joint Research Centre is applied to a specific use case in the context of smart grids. The selected use case examines a flexibility activation mechanism in a power grid system and includes DSO SCADA, Remote Terminal Unit and flexibility source, interacting to support a voltage regulation service. The adopted test bed consists of a real-time power grid simulator, a communication network emulator and use case actors' models in a hardware-in-the-loop setup. The breakdown of the interoperability testing problem is accomplished by mapping the use case to the SGAM layers, specifying the Basic Application Profiles together with the Basic Application Interoperability Profiles (BAIOPs) and defining the design of experiments to carry out during the laboratory testing. Furthermore, the concepts of inter-and intra-BAIOP testing are formalized to reflect complementary interests of smart grid stakeholders. Experimental results prove the applicability of the methodology for testing the interoperability of large-scale and complex smart grid systems and reveal interesting features and possible pitfalls which should be considered when investigating the parameters responsible for the disruption of a system interoperability.Energies 2020, 13, 1648 2 of 25 as the main challenge for the deployment of the SGs, in which technologies and companies from very diverse domains converge: electricity technologies at large, grid measurement, protection and control, Distributed Energy Resource (DER) management, industrial automation and power electronics, Information and Communication Technologies (ICTs) at large, building and home automation, smart metering. This diversity of domains gives place to the overlapping of many standards and different standardization approaches.There is quite an extensive research work in IOP literature focusing on different SG domains with respect to their relevant standards. In this regard, and in response to the European M/490 mandate, the "CEN-CENELEC Smart Grid Set of Standards" document [3] provides a comprehensive list of standards for supporting and fostering the deployment of SG systems in Europe facilitating interoperable solutions. In particular, it provides any SG stakeholder with a selection guide in order to set out the most appropriate (existing and upcoming) standards to consider, depending on the specific SG system and the Smart Grid Architecture Model (SGAM) layer of interest.Paper [4] explores the modelling structure of IEC 61850 standard for microgrid protection systems and highlights the IOP issues that might arise from the ambiguity and flexibility in IEC 61850 and proposes a framework for microgrid protection which can include an IOP testing to check interactions between different devices. However, it does not elaborate how the IOP testin...