Pachydermoperiostosis (PDP) is characterized by finger clubbing, periostosis and peculiar skin involvement (pachydermia, seborrhea and folliculitis). The aim of our work was to determine the occurrence of dermatological symptoms in patients with PDP and their relatives, and to study ultrastructural skin changes in the complete and incomplete forms of the disease. A genetic and cytogenetic study was performed in order to identify the mechanism of transmission, to discover possible links to other genetic and non-genetic diseases and to determine the chromosomal complement and eventual chromosomal anomalies. Pachydermia was the most frequent skin alteration together with seborrhea; folliculitis was present in five patients. In the relatives mild pachydermia was detected in 2 out of 26, while seborrhea was present in 6 subjects. Light microscopic observation showed acanthotic epidermis and endothelial hyperplasia in the dermis with partial occlusion of the lumen, lymphohistiocytic infiltrate, and thickening and packing of collagen fibers. Electron microscopy showed fibroblast activation with increased fibrillogenic activity as shown by hypertrophic Golgi complexes and rough endoplasmatic reticulum with cisternae filled with microfibrils. Endothelial cells partially or completely occluded the capillary lumen and presented an increased amount of Weibel Palade bodies. These data show that skin involvement in PDP is a prominent feature, that sometimes these symptoms may also be present in their relatives, and that endothelial and fibroblast activation is present in the skin. Unfortunately the cytogenetic study did not provide any information about possible karyotype abnormalities.