The pathogenicity of the human c-erbB-2 oncogene was evaluated in transgenic mice. A DNA sequence comprising the promoter-enhancer region of the MMTV LTR and a constitutively activated allele of the human c-erbB-2 growth factor receptor gene was introduced into the germ line of mice. Expression of the transgene was observed in kidney, lung, mammary gland, salivary gland, Harderian gland, and in epithelial cells of the male reproductive tract. All transgenic mice expressing the c-erbB-2 receptor died within four months of birth. Histopathological analysis suggests that preneoplastic lesions in kidney and lung most likely caused organ failure and the early death of the transgenic mice. Focal dilatation and atypical proliferation of the tubular epithelial cells was found in the kidney. These hyperplastic lesions were found adjacent to normal tubules. Immunohistochemistry showed that normal renal structures were completely negative for c-erbB-2 protein expression. Atypical pseudopapillary proliferation of bronchial and bronchiolar epithelial cells narrowed the bronchial lumen in lung. Alveoli appeared normal. The expression of c-erbB-2 protein was strictly limited to the proliferating epithelial cells and not detected in normal tissue. The mammary glands of two parous mice were underdeveloped, lacking lobular-alveolar structures and were lactation deficient. Only a few ducts were interspersed in the fat pad. A virgin mouse developed a focal adenocarcinoma infiltrating the mammary fat pad. Expression of the c-erbB-2 protein was enhanced in the proliferating epithelial cells. Transgenic males were sterile. Epithelial hyperplasia and hypertrophy in the epididymis, vas deferens and seminal vesicles was found. The transgene is not uniformly expressed in the tissues where the MMTV LTR is transcriptionally active. The scattered transgene expression invariably coincides with epithelial hyperplasia.