Myeloperoxidase (MPO) is an oxidative enzyme expressed in polymorphonuclear leukocytes. It is involved in the defence against periodontal bacteria, and is also able to mediate inflammatory tissue destruction in periodontal disease. A G/A polymorphism in the promoter region of the MPO gene at position -463 has been assumed to exert profound effects on the expression of the enzyme. It is the aim of this study to evaluate whether this polymorphism may influence the risk of periodontal diseases. A total of 3148 subjects were randomly selected from the general population in the SHIP study (Study of Health in Pomerania). Periodontal status, health-related and socio-economic items were assessed. All subjects aged 40-60 years (n = 1103) were included in this study, and 1083 genotyped for the MPO -463 G/A polymorphism by PCR and RFLP methods. The genotype frequencies determined were homozygous wild type G/G 65.9% (95% CI 63.5-68.6), heterozygous A/G 31.4% (28.8-34.4), and homozygous variant A/A 2.7% (2.0-3.8). Only female subjects have a significantly reduced risk of severe periodontal disease when bearing the variant genotypes A/G or A/A. In female subjects the reduction in periodontal risk was significant for non-smokers (OR = 0.48; 95% CI 0.23-0.96); the smoke-related increase in risk was also reduced (OR = 0.50; 95% CI 0.22-1.10). When adjusted for age, smoking, and education the odds ratios were calculated as 0.52 (P = 0.01) and 0.97 (P = 0.90) for female and male subjects, respectively. The results of this study confirm the assumption that the MPO -463A allele variants are protective in the pathogenesis of periodontal diseases. This holds true only with women but not with men. The results are discussed with respect to the known influences of sexual hormones on MPO activity.