Cases of pathologically changed bone might constitute a diagnostic pitfall and frequently need histological methods to be etiologically properly evaluated. With micro-computed tomography (μCT), a new epoch of 2D and 3D imaging has been launched. We evaluated the diagnostic investigation of this analytical method versus well established histological investigations of historical human bone. Pathological changes due to various etiologies (infectious, traumatic, endocrinological, neoplasia) observed in autopsy-based macerated human skulls (Galler Collection, Natural History Museum Basel, Switzerland) were investigated by μCT and compared with histological thin ground sections using polarized light. Micro-CT images visualize the architecture of the bone with high spatial resolution without preparation or destruction of the sample in the area to be sectioned. Changes in the bone surfaces as well as alterations of the diploë can be assessed. However, morphological patterns caused by reactive response, such as typical arrangements of collagen fibers, can only be visualized by the microscopic investigation of thin ground sections using polarized light. A great advantage of μCT is the high number of slices obtained so that spatial differences within the areas of the specimen become visible. Micro-CT is a valuable tool for the diagnosis of vestiges of skull bone diseases. Its advantages over histology are the fast, automated image acquisition and the fact that the specimen is not completely destroyed. Only excision of the area to be scanned is necessary, if the specimen is too large to be scanned as a whole. Further, the 3D visualization of the micro-architecture allows an easy orientation within the sample, for example, for the choice of the location of the histological slices. However, the need to differentiate woven from lamellar bone still makes histology an indispensable method. Am J Phys Anthropol, 2007. © 2007 Wiley-Liss, Inc.