Myeloperoxidase (MPO) is a metabolic/oxidative enzyme found in neutrophils and monocytes that contributes to pulmonary carcinogenesis through activation of specific procarcinogens including benzo[a]pyrene intermediates, 4-aminobiphenyl and the arylamines. There is a G-->A polymorphism located in the 5' untranslated region of the MPO gene that may be responsible for reduced transcriptional activity due to the decreased binding affinity for the SP1 transcription factor. Individuals with one or two copies of the A-allele may be afforded protection due to decreased transcriptional activity of MPO and subsequent decreased metabolic activation of procarcinogens. Previous studies have reported a range of protective effects in different ethnic populations. We employed a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) assay to identify the MPO genotypes in 375 lung cancer cases and 378 healthy controls, all of whom were Caucasian. Our results demonstrate a reduced risk of lung cancer when the A-allele genotypes (G/A+A/A) were combined (odds ratio (OR)=0.66; 95% confidence interval (CI) 0.49-0.90). We also noted a protective effect (OR=0.63; 95% CI 0.45-0.87) in ever smokers with the A-allele genotypes which was not evident in never smokers (OR=1.14; 95% CI 0.42-3.11). We observed an incremental decrease in the protective effects as cigarette pack-years increased. Thus, lightest smokers were provided the greatest protection. When the data were stratified by gender, there was a statistically significant reduced risk of lung cancer among men (OR=0.55; 95% CI 0.36-0.84), but not among women (OR=0.81; 95% CI 0.55-1.26) for the A-allele genotypes. Lastly, an age effect was evident only in men but not women. The protective effects of the A-allele genotypes decreased with increasing age. This report provides further support for the hypothesis that a single nucleotide polymorphism in the MPO gene is a protective factor in lung cancer carcinogenesis.