To assess the role of various risk factors in the pathogenesis of chronic obstructive lung disease (COLD), 163 men and women were followed for approximately 6 yr. Subjects were either community volunteers or relatives of patients with antitrypsin deficiency (PiZ or MZ phenotype). At the onset of the study no subject was receiving medical care for COLD. Covariance analysis revealed that expiratory airflow rates declined excessively in male subjects who had the PiMZ phenotype and reported a family history of lung disease. In subjects with the combination of characteristics, loss of lung function approximated that reported in subjects who have established COLD. In several such subjects, abnormalities have progressed so that they now require treatment. Changes in lung function were less striking in the presence of only 1 or 2 of the 3 risk factors studied. These findings demonstrated that the characteristics of the population being studied can influence the outcome of an investigation. This effect may help account fo the conflicting results of previous investigations designed to assess the role of the PiMZ phenotype in the pathogenesis of COLD.