Alpha-1-antitrypsin was examined in the serum from 121 Down's syndrome families. Variant phenotypes (non-M) were increased in frequency in parents (15%) and in their affected children (19%) compared to frequencies of 8-10% in two control groups (p less than 0.001). Variant parental Pi phenotypes were found in 19 mothers and 10 fathers of Down's patients. Parental origin of the extra chromosome 21 was known in 34 families and was maternal in 26 instances. In seven families where parental origin of the extra chromosome was known, a variant Pi phenotype was inherited from the parent contributing the extra chromosome in four families and from the parent not contributing the extra chromosome in three families, indicating that there is no simple correlation between the Pi variant and nondisjunction. The increase in Pi variant in Down's syndrome families was independent of maternal age.