To gain insight into the variable expression of lung disease in α1-antitrypsin (α1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25–75), total serum α1AT, oxidized serum α1AT, and total serum immunoglobulin E (IgE) were measured in α1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total α1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25–75, and oxidized α1AT are moderately influenced by Pi type. The effect of genotype-by-environment interaction between Pi type and pack-years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi × pack-years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi × age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi × pack-years interaction effect on FEV1 which Pi Z subjects ascertained for other reasons demonstrate. The effect of the Pi × pack-years interaction on FEV1 was no longer significant on a transformed scale, (FEV12,) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi × packs-years interaction effect on FEF25–75 to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype-by-environment interaction analyses into the study of the variable expression of lung disease in Pi Z individuals. © 1992 Wiley-Liss, Inc.