Myeloperoxidase (MPO) is an haemoprotein that metabolizes tobacco smoke procarcinogens such as benzo(a)pyrene and aromatic amines into highly reactive intermediates. A polymorphism in the MPO promoter (-463G>A), resulting in lower expression, was previously associated with a decrease in lung cancer risk. In this study, the MPO gene was analysed for new polymorphisms by denaturing high-performance liquid chromatography and sequencing on a panel of 48 subjects. Subsequently, the association between newly described polymorphisms, the -463G>A single nucleotide polymorphism (SNP) and lung cancer risk was investigated in a case-control study comprising 245 Caucasian cases and 249 Caucasian controls. Genetic polymorphisms were found in exons 2 (V53F), 6 (M251T), 7 (A332V), 11 (I642L) and 12 (I717V), with allelic frequencies of 6.0%, 1.8%, 1.8%, 0.2% and 1.8%, respectively. A new polymorphism located in the intron 11 3' splice site was found (0.4%). The known -463G>A polymorphism (24.0%) and four new polymorphisms in promoter region were also detected. No correlation between these new polymorphisms and lung cancer risk was found. For the -463G>A polymorphism, no modification of lung cancer risk was observed for either the G/A genotype [odds ratio (OR) 1.19; 95% confidence interval (CI) 0.8-1.8] or the A/A genotype (OR 0.97; 95% CI 0.4-2.6). Linkage analysis showed a strong disequilibrium between -463G>A polymorphism and exonic SNPs. However, the distribution of reconstructed haplotypes did not differ significantly between cases and controls. Further studies need to be performed to investigate the role of these polymorphisms in others diseases.