Although the development of chronic obstructive pulmonary disease (COPD) in smokers shows genetic susceptibility, only alpha1-antitrypsin deficiency has been identified as a definite genetic risk factor. There have been three previous studies in which associations between Gc-globulin phenotypes and COPD have been investigated. Although some data suggest an association, the results were inconclusive. Because smoking is the major risk factor for COPD, it may have been a confounding factor in previous studies. We have investigated Gc-globulin genotypic frequencies among 75 COPD patients and 64 nonobstructed controls. Both groups had significant smoking histories: pack-years (mean +/- SD) of 52 +/- 30 and 48 +/- 27, respectively. The results show that homozygosity for the Gc2 allele is protective against COPD (OR = 0.17, 95% CI = 0.03 to 0.83). There were no differences between genotypes for lung elastic recoil values or for the level of upstream airway resistance. Gc-globulin can enhance complement (C5a)-mediated neutrophil chemotaxis. Because neutrophils play a role in parenchymal destruction and airway inflammation, we examined whether Gc-globulin's ability to enhance neutrophil chemotaxis varied with genotype. We found no difference among genotypes with respect to neutrophil chemotaxis suggesting that the protective effect of the Gc2 allele is mediated through a different mechanism.