A line of transgenic mice that develops submandibular gland adenocarcinoma of intercalated duct origin was established. In these mice, the oncogene SV40 T antigen (Tag) is expressed from the neonatal submandibular gland secretory protein b (Smgb) gene promoter. This hybrid gene directs expression of the oncoprotein to neonatal submandibular gland proacinar and terminal tubule cells and to intercalated ducts of the adult gland. Transgene expression resulted in duct luminal cell hyperplasia as early as 20 to 30 days postnatally, which progressed to dysplasia by 3 to 4 months of age. Marked dysplasia and in situ carcinoma were evident at 4 to 6 months of age. All histologic changes were more pronounced in males. Submandibular gland adenocarcinoma developed stochastically in more than half of the adult male mice by 12 months of age (average age: 10.8 months, range: 6 to 13.5 months). Tag expression persisted in in situ carcinoma and all tumors. Using a combination of immunocytochemical and ultrastructural criteria, submandibular gland dysplasia and tumors were found to originate from intercalated ducts. The dysplastic ducts and adenocarcinoma in Smgb-Tag mice were morphologically similar to previously reported Tag-induced dysplasias of striated ducts and granular convoluted tubules and a Tag-induced adenocarcinoma of striated duct origin<zaq;1. These findings demonstrate that salivary gland dysplasias and tumors of similar histologic appearance can arise from distinct differentiated cell types. Analysis of the molecular changes accompanying tumor formation in Smgb-Tag mice could increase knowledge of human salivary gland tumorigenesis.