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A role for endothelial nitric oxide synthase (NOS3) in the susceptibility of individuals with α1-antitrypsin (α1AT) deficiency to destructive lung disease was evaluated. Six polymorphic sites were identified within the NOS3 gene (i.e., -924A/G, -788C/T, -691C/T, 774C/T, 894G/T, and 1998C/G). The genotype distribution was determined in 339 patients and 94 control individuals. Frequency of the 774T allele in severely affected individuals was 0.417 versus 0.269 in control subjects (P = 0.018), whereas the 894T allele frequency was 0.427 versus 0.280 in control subjects (P = 0.024). Patients with less severe lung disease had the 774T and 894T allele frequencies of 0.289 and 0.344, respectively, similar to frequencies in a control group (P > 0.3). No direct correlation between pulmonary function and five other NOS3 polymorphisms was observed. Thus, functional allelic variants that are in linkage disequilibrium with the 774C/T and 894G/T may be present in the specified genomic area. These data are consistent with a modulatory role for NOS3 in destructive lung disease associated with α1AT deficiency.