The α₁-protease inhibitor, or α-antitrypsin (AAT), a major plasma inhibitor of leukocyte elastase and bacterial proteases, is encoded at the PI locus on chromosome 14 (14q24.3–q32.1)¹. A deficiency of AAT in individuals homozygous for the PI Z allele occurs in about 1 in 2,000–8,000 Caucasians² and is associated with an increased risk of early adult onset emphysema³ and liver disease in childhood⁴. We have now used DNA polymorphisms associated with the AAT gene to investigate the origin of the PI Z allele. Using two genomic probes⁵ extending into the 5′ and 3′ flanking regions, respectively, we have identified eight polymorphic restriction sites. Extensive linkage disequilibrium occurs throughout the probed region with the PI Z allele, but not with normal PI M alleles. The Z allele occurs mainly with one haplotype, indicating a single, relatively recent, origin in Caucasians.