Patients with human epidermal growth factor receptor 2 (HER-2) overexpressing breast carcinomas have a more aggressive clinical behavior and their tumors are often hormone receptor negative. However, the recently introduced anti-HER-2 antibody trastuzumab has been proven to improve the survival and controls the disease in a significant proportion of these patients. Therefore, the analysis of HER-2 in patients with breast cancer has become an important and routine test to select those who may benefit from the gene-based targeted therapy trastuzumab (herceptin). There is good correlation between HER-2/neu protein overexpression and HER-2 gene amplification in breast cancer. However, inconsistent results have been reported in the rate of HER-2/neu protein overexpression in other malignant neoplasms. Furthermore, only rare studies have investigated the correlation between the HER-2/neu protein overexpression and the status of HER-2 gene in these tumors. We investigated the HER-2 gene and protein status in several cases of Paget disease of the nipple and vulva by using a chromogenic in situ hybridization assay and immunohistochemistry. We find that the majority of the Paget disease of the breast demonstrate HER-2 gene amplification, whereas most of the extramammary Paget disease lack HER-2 gene amplification. In addition, our results show a good correlation between HER-2/neu protein overexpression and HER-2 gene amplification in Paget disease of the nipple, but we were unable to confirm this correlation in HER-2/neu protein overexpressing Paget disease of the vulva.