Myeloperoxidase (M PO) is a phase I enzyme that can bioactivate many specific procarcinogens, including polycyclic aromatic hydrocarbons and aromatic amines. The MPO gene contains a common single nucleotide polymorphism, for which the -463G>A substitution within the promoter region has been shown to reduce MPO expression and activity. We investigated the association between the MPO -463G>A polymorphism and lung and prostate cancer in a Turkish population. MPO genotypes in the study populations were determined using polymerase chain reaction-based restriction fragment length polymorphism assay. The allelic frequency was significantly different between the cases and controls for lung cancer (p=0.02), but not prostate cancer (p=0.30). No significant difference was noted between the lung and prostate cancer cases and control populations in terms of genotype distribution (p=0.07, p=0.53, respectively). Control groups of lung and prostate cancer were in Hardy-Weinberg equilibrium (p=0.87 and p=0.41, respectively). To determine the protective effect against lung cancer among individuals with the -463A allele, C/A and A/A genotypes were combined. Comparison of the GIG and C/A + A/A genotypes between the lung cancer cases and control groups showed a statistically significant relationship (p=0.032, OR=0.60, 95% CI 0.38-0.95). No gender-specific difference was found in terms of genotype distribution between the lung cancer patients and the controls (female, p=0.20; male, p=0.34). In the case of smokers, a difference in genotype distribution between the lung cancer patients and the controls was statistically significant (p=0.02), although this difference was not statistically significant for non-smokers (p=0.90). Overall, no statistically significant difference was found between the prostate cancer cases and the controls in terms of genotype combination (p=0.46, OR=0.83, 95% CI 0.51-1.36). Additionally, in smokers and non-smokers, no significant relationship was determined between the prostate cancer patients and the control population (p=0.21, p=0.91, respectively). These results suggest that the MPO -463A allele significantly contributes to a protective effect overall and in smokers against lung cancer.