Myeloperoxidase is a lysosomal enzyme found in high concentrations in human lung due to recruitment of neutrophils. Myeloperoxidase activates benzo[a]pyrene as well as aromatic amines in tobacco smoke and generates carcinogen-free radicals. A single base substitution (G to A) in the promoter region of the myeloperoxidase gene has recently been demonstrated to markedly reduce transcription. We developed an RFLP/PCR assay to test the hypothesis that the allele favoring lower transcription (A allele) reduces the risk of lung cancer. Among population controls, 7.8% of 459 Caucasians and 9.4% of 244 African-Americans inherited two copies of the A allele. Caucasians with the A/A genotype were at 70% reduced risk of lung cancer (odds ratio, 0.30; 95% confidence interval, 0.10-0.93; P = 0.04; 182 cases). A lesser reduction in risk was observed for African-Americans with this genotype (odds ratio, 0.61; 95% confidence interval, 0.26-1.41; 157 cases). Individuals who inherit two copies of an allele that reduces transcription of the myeloperoxidase gene may be at decreased risk of lung cancer.