RATIONALE: Increased oxidative stress is involved in chronic obstructive pulmonary disease (COPD); however, plasma and bronchial lining fluid contains the antioxidant extracellular superoxide dismutase. Approximately 2% of white individuals carry the R213G polymorphism in the gene encoding extracellular superoxide dismutase, which increases plasma extracellular superoxide dismutase 10-fold and presumably also renders bronchial lining fluid high in extracellular superoxide dismutase. OBJECTIVE: We tested the hypothesis that R213G reduces the risk of COPD. METHODS: We studied cross-sectionally and prospectively (during 24 yr) 9,258 individuals from the Danish general population genotyped for R213G. MEASUREMENTS: We determined plasma extracellular superoxide dismutase concentration, pulmonary function and COPD diagnosed by means of spirometry or through national hospitalization and death registers. MAIN RESULTS: In the general population, 97.5% were noncarriers, 2.4% were heterozygotes, and 0.02% were homozygotes. Among R213G noncarriers, extracellular superoxide dismutase plasma concentration was 148+/-52 and 142+/-43 ng/ml (mean+/-SD) in individuals with and without COPD (Student's t test, p=0.02). Among heterozygotes, corresponding concentrations were 1,665+/-498 ng/ml and 1,256+/-379 (p<0.001). The adjusted odds ratio for spirometrically diagnosed COPD in heterozygotes versus noncarriers was 0.5 (95% confidence interval: 0.3-0.9). After stratification, the equivalent adjusted odds ratio was 1.5 (0.3-6.6) among nonsmokers and 0.4 (0.2-0.8) among smokers (p value for interaction=0.10). The adjusted hazard ratio for COPD hospitalization or death during follow-up in heterozygotes versus noncarriers was 0.3 (0.1-0.8). CONCLUSIONS: Extracellular superoxide dismutase R213G heterozygosity protects against development of COPD in the Danish general population. This was observed in smokers, but not in nonsmokers.