The human immunodeficiency virus tat protein, a transactivator of viral and cellular genes, is suspected to be involved in the pathogenesis of acquired immunodeficiency syndrome-associated tumors. We report that transgenic mice carrying a recombinant DNA containing BK virus early region and the human immunodeficiency virus tat gene develop skin leiomyosarcomas, squamous cell papillomas and carcinomas, adenocarcinomas of skin adnexa, glands, and B-cell lymphomas. Although the incidence of hepatocellular carcinoma is low, most animals show a liver cell dysplasia of variable degree. These mice are also affected by skin lesions resembling the early stages of Kaposi's sarcoma. The transgene was detected intact in all the organs of transgenic mice, generally as multiple tandemly integrated copies. BK virus early region and tat were expressed in essentially all tissues and organs of BK virus/tat transgenic mice. This transgenic mouse model is representative of the systemic involvement of tat in human immunodeficiency virus natural infection and may be applied to investigate the role of tat in malignancies associated to acquired immunodeficiency syndrome, to study Kaposi's sarcoma pathogenesis and cell of origin, to characterize preneoplastic conditions established by tat in the skin and liver, and to assess in vivo the efficacy of antiangiogenic and anti-tat-specific drugs.