To gain insight into the variable expression of lung disease in α1-antitrypsin deficiency, two pulmonary function tests, FEV1 and FEF25_75, were examined in α1-anti-trypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated higly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV1 but was shown for FEF25–75. For FEV1, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV1; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial tra