Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects against oxidative stress which is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). Three single nucleotide polymorphisms and 1 triplet repeat polymorphism are found in the promoter region of the Nrf2 gene. Molecular haplotyping of the Nrf2 promoter region was performed using DNA obtained from the peripheral blood of 69 COPD patients. The luciferase activities of Nrf2 promoter constructs containing all possible combinations of the 4 polymorphisms were determined and found to differ among the 16 haplotypes.The haplotypes isolated from the subjects were divided into 3 groups (L: low; M: medium; H: high) on the basis of luciferase activities. The proportions of subjects belonging to global initiative for chronic obstructive lung disease stage 3 or 4 decreased from the group with the LL haplotype to that with the HH haplotype. Presence of the LH or MM haplotype (hazard ratio, 3.36; 95% confidence interval, 1.16–9.69), gender (0.13; 0.02–0.67), and post-bronchodilator FEV1 value of predicted (0.95; 0.91–0.99) are significant predictors of respiratory failure development.The haplotype of the Nrf2 gene promoter affects its activity, and is associated with the severity and the development of respiratory failure in COPD.