Nitric oxide (NO) plays critical role in endothelial dysfunction and oxidative stress in COPD, pointing to the significance of endothelial nitric oxide synthase gene (eNOS) variants. We investigated the association of -786T/C, -922A/G, 4B/4A, and 894G/T polymorphisms of eNOS with the disease and its impact on nitrite and malonaldehyde levels in 190 COPD patients and 134 healthy controls, all smokers. The -786C, -922G and 4A alleles were significantly over-represented in patients (p = 0.02, p = 0.02, and p = 0.03, respectively). The haplotypes, -786C:4A, 4A:894G, -786C:894G, and -786C:4A:894G were significantly over-represented in patients (p < 0.0001, p = 0.02, p = 0.02, and p < 0.0001, respectively), whereas, haplotypes, -786T:4B, 4B:894G, -786T:894G, and -786T:4B:894G were significantly under-represented in the patients (p < 0.0001). The patients had significantly increased levels of nitrite (p = 0.003) and malonaldehyde (p < 0.0001). Combination of genotypes containing -786C and 4A alleles were greater in patients (p ≤ 0.05), and these combinations associated with decreased FEV1 value and nitrite level (p = 0.03 and p = 0.04, respectively) and with increased malonaldehyde levels (p = 0.02). The eNOS -786C, -922G, and 4A alleles, these alleles associated haplotypes and genotype combinations were over-represented in patients. The variants and their combinations of four polymorphisms of eNOS contribute to disturbed pulmonary function and oxidative stress in COPD. © 2007 Elsevier Inc. All rights reserved.