A late pre-Angkorian period, c. 350 BC - 200 AD, cemetery has been excavated in the village of Phum Snay, in northwestern Cambodia. In addition to the cemetery sample, a large sample of stratigraphically unprovenanced human skeletal material was uncovered in the village through extensive looting over the last 5–10 years. Both sample sets were available for study but the latter is comprised of only isolated bone elements. The differential diagnosis of the cause of lesions in one isolated cranial vault from this sample is presented here. Widespread, primarily lytic, lesions are concentrated on the frontal and anterior parietal bones, with an additional large lesion on the occipital bone. Lesions vary in size ranging from approximately 5–30 mm in diameter. A detailed description of these lesions is given and a differential diagnosis is presented that includes infectious disease, such as osteomyelitis, tuberculosis and treponemal disease, and also several forms of cancer including metastatic carcinoma, meningioma and multiple myeloma, and finally Langerhans Cell Histiocytosis. The diagnosis is difficult, given the lack of material, but it is suggested that one of the forms of Langerhans Cell Histiocytosis is the most likely candidate. The presence of such large and diffuse lesions is unusual in prehistoric Southeast Asia so the significance of this is also discussed. Copyright © 2010 John Wiley & Sons, Ltd.