Quantification of the major plasma protease inhibitors and genetic typing of alpha1-antirypsin were done in 107 patients with chronic obstructive pulmonary disease and in 91 control subjects with normal ventilatory function who were similar with respect to age, race, and sex. There was a significant increase in frequency of the PiZ gene and the Pi MZ phenotype of alpha1-antitrypsin among the patients when compared with the control subjects. No evidence for a primary deficiency of any other antiprotease was found; however, the mean concentration of inter-alpha-trypsin inhibitor was significantly lower in the patients than the control subjects, and moderate deficiency of alpha1-antichymotrypsin was noted in a few patients. These data indicate an increased risk of developing chronic obstructive pulmonary disease in persons with the Pi MZ phenotype of alpha1-antirypsin and suggest a possible relationship between these diseases and low serum concentrations of inter-alpha-trypsin inhibitor.