The silent sinus syndrome is characterized by painless enophthalmia and hypotropia caused by chronic atelectasis of the maxillary sinus with onset in adulthood, typically between the third and the fifth decade of life. It is increasingly diagnosed as a result of today’s widespread use of computed tomography (CT). The phenomenon was originally described in 1964 (Montgomery, 1964), while the term “silent sinus syndrome” was later introduced by Soparkar and colleagues in 1994. The pathogenic mechanism appears to involve chronic maxillary sinus obstruction with hypoventilation as well as the development of negative pressure within the sinus. While studying literature on crania of Egyptian royal families, photographs of the skull of Queen Meresankh III caught our attention because of the unusually shaped orbits, skull vault and suborbital areas. A retrospective craniometric analysis clearly suggests a pathological condition. Materials & Methods: In this multimodal, interdisciplinary study we reassessed the excavation report of Queen Meresankh III’s mastaba tomb in Giza (Egypt) as well as a publication in the anatomical record (Dunham and Simpson, 1974). Precise craniometric measurements were obtained by application of a three-dimensional (3D) image reconstruction method, which was compared to reference data from two different databases. A differential diagnosis was established in consensus by the authors with regard to the found pathologic craniometric measurements as well as to the biographic information available from the historical sources. Results: Queen Meresankh III was an Ancient Egyptian queen of the 4th Dynasty (Old Kingdom, lifespan c. 2620/10-2570 BC). Her lifespan is reconstructed from the death date mentioned in her tomb. According to our measurements, her cranium shows unusual features and measurements outside the normal range. The maxillary sinuses are bilaterally reduced and the zygomatic arch is altered with a diminished lateral extent. The width of the skull is pathologically increased, while the cranial capacity is in a normal range. The orbit widths compare well with existing data, while orbit heights exceed ranges of normal women by more than 2 standard deviations. Conclusion: On account of the presented evidence, a retrospective diagnosis of Silent Sinus Syndrome for Queen Meresankh III may be reasonably postulated, making it the world’s oldest case of the Silent Sinus Syndrome. Other considered differential diagnoses could either be ruled out based on craniometric measurements or biographic information. The impossibility to carry out further analyses on the queen’s mortal remains at present, however, suggests caution in definitive interpretations. Should additional tests one day be possible to carry out, a more refined diagnostics could be achieved.