Heme oxygenase (HO-1) acts against oxidants which are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT)n repeat polymorphism in the HO-1 gene promoter can modulate the gene transcription in response to oxidative stress. We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative agression (smokers). We genotyped 749 French subjects (20-44 years, 50% men, 40% never-smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by FEV1 (Forced Expiratory Volume in 1 second) and FEVI/FVC (Forced Ventilatory Capacity) ratio. We compared long (L)-allele carriers ((GT)n ≥ 3 repeats for one or two alleles) to non-carriers. Cross-sectionally, in 2000, L-allele carriers showed lower FEVI/FVC than non-carriers. During the 8-year period, the mean annual FEVI and FEVI/FVC declines were -30.9±31.1 ml/year and -1.8±6.1 unit/year, respectively. FEV1/FVC decline was steeper in L-allele carriers than in non-carriers (-2.6±5.5 vs -1.5±6.4, p=0.07). There was a strong interaction between allele L and smoking. In 2000, allele L was associated with lower FEV1 and FEV1/FVC in heavy smokers (≥20 cig/day) only (p for interaction=0.07 and 0.002 respectively). Baseline heavy smokers carrying allele L showed the steepest FEVI decline (-62.019.5 ml/year) and the steepest FEV1/FVC decline (-8.8±5.4 unit/year) (p for interaction=0.009 and 0.0006).These results suggest that a long (L) HO-1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction.