alpha 1-Antitrypsin (alpha 1AT) is an abundant serum protein whose major site of synthesis is in the hepatocyte. alpha 1AT transcripts are also present, albeit at a lower level, in a variety of other human tissues. This pattern of expression is partly related to initiation of transcription at sites with distinct tissue specificities. The mouse alpha 1AT gene, in contrast, is more strictly liver specific in its expression. To explore the regulation of the alpha 1AT gene we have microinjected a cosmid insert carrying the human gene into fertilized mouse eggs. In three lines obtained from transgenic mice, inheritance of copies of the human gene is accompanied by a high serum concentration of the human protein. Human alpha 1AT RNA accumulates to the highest level in liver of transgenic animals. The presence of transcripts in other tissues indicates that the human pattern of expression is maintained, whereas the temporal activity of the introduced gene parallels that of the endogenous one during mouse embryogenesis.