The past decade has witnessed an increased interest in what are called “medically unexplained syndromes” (MUS). We address the question of whether structuring the domain knowledge for MUS can be achieved by applying the principles of Ontological Realism in light of criticisms about their usefulness in areas where science has not yet led to insights univocally endorsed by the relevant communities. We analyzed whether the different perspectives held by MUS researchers can be represented without taking any particular stance and whether existing ontologies based on Ontological Realism can be further built upon. We did not find refutation of the applicability of the principles. We found the Ontology of General Medical Science and Information Artifact Ontology to provide useful frameworks for analyzing certain MUS controversies, although leaving other questions open.