This paper uses macroscopic and radiological examinations to provide differential diagnoses of pathological lesions in the well-preserved skeleton of a young male from the medieval site of Zalavár in South-West Hungary. Macroscopic inspection of the skeleton revealed conspicuous thickening of the tibiae and fibulae with ‘tree bark’ appearance of the cortex. Periosteal proliferations are also found on the calcanea and on the posterior part of the femora. The metatarsals showed bony proliferation and bone dissolution. No alteration of the axial skeleton or the skull was noted. Radiographs showed thickening of the cortex of tubular bones due to a multilayered type of periosteal apposition. The likelihood of these symptoms being the result of melorheostosis, hypervitaminosis A, fluorosis, thyroid acropachy, endosteal hyperostosis, tuberculosis (TB), hypertrophic osteoarthropathy (HOA), treponematosis and leprosy is reviewed. None completely explains the entire spectrum of pathological lesions in the current individual, but the individual may have suffered from two co-existent diseases. As a clinical entity, the changes in the metatarsals are compatible with leprosy, whereas the periosteal proliferations of the lower limbs point to a diagnosis of HOA as a secondary syndrome. Thus, a combination of leprosy and TB is suggested as a potential diagnosis. Although not definitive, our differential diagnosis was able to exclude a number of conditions producing periosteal apposition. Copyright © 2011 John Wiley & Sons, Ltd.