A group of 52 α₁-antitrypsin-deficient individuals of phenotype Pi Z and 117 of their relatives underwent a protocol including pulmonary function testing, completion of a questionnaire, and blood donation. Our population permitted a minimum frequency estimate (7 × 10⁻⁴) for Pi null alleles. Five quantitative phenotypes were measured, including FEV₁ FEF_25–75, total serum α1AT, oxidized serum α1AT, and total serum IgE. We found that (1) total α1AT levels were higher in Pi Z subjects with lung function impairment (FEV₁ ⩽ 65% of predicted) than in Pi Z subjects who were not impaired; (2) Pi Z subjects with lung function impairment had elevated serum levels of oxidized α1AT; and (3) IgE levels were relatively elevated in first-degree Pi MZ relatives of impaired Pi Z subjects. Moreover, FEV₁ tended to be relatively reduced in heterozygous parents of impaired Pi Z subjects, suggesting that a subset of Pi MZ individuals are at risk for development of lung disease because of familial factors. These results represent an initial step toward the development of intermediate phenotypes that will be predictive of a severe course in α1AT deficiency; they suggest that, in addition to cigarette smoking, atopic predisposition and undetermined familial factors may be important codeterminants of lung disease progression.