Normal and mutant human alpha-1-entitrypsin genes were cloned from a PiMZ heterozygous individual. Nucleotide sequence comparison demonstrated a T to C transition in exon III and an C to A transition in exon V of the PiZ gene. A 14.4 kb DNA fragment containing the entire PiM gene plus 2 kb of 5' and 3' flanking genomic DNA sequences was introduced into the germ line of mice and five F ₀ transgenic lines were established. Transgenic F ₁ progeny from F ₀ parents exhibited high levels of human alpha-1-antitrypein protein in their plasma. The human gene was expressed primarily in liver of the transgenic mice as it is in man. However, expression of the human alpha-1-antitrypsin gene was also observed in kidneys of the tranagenic mice, which led to the observation that the endogenous mouse gene is also expressed in the kidney. These data indicate that cis-acting elements within or proximal to the human alpha-1-antitrypsin gene are able to direct its in vivo transcription with a high degree of tissue specificity.