S100A8, the light subunit of calprotectin, has been known to be associated with periodontal inflammation. The present study looked to detect whether three polymorphisms in the upstream region of the S100A8 gene are correlated with periodontitis. Three hundred and twenty one subjects, including chronic periodontitis (CP) patients, aggressive periodontitis (AgP) patients and periodontally healthy controls, were recruited. The SNPs rs3795391, rs3806232 and rs3885688 were analyzed by PCR-RFLP analysis. No person carried the rs3885688 polymorphism in this cohort. For the other two polymorphisms, the combined effects of genotype/allele and gender were shown to be associated with the risk of periodontitis using multivariate logistic regression analysis. The G+ genotype/G allele may be considered to exert a significant protective effect in males against AgP (Genotype: rs3795391: P= 0.032, rs3806232: P= 0.017; Allele: rs3795391: P= 0.024, rs3806232: P= 0.013). Although the combined effects of genotype and gender on CP susceptibility were not observed for these two polymorphisms, there does seem to be increased risk of CP in males with allele A compared to females with allele A (rs3795391: P= 0.008; rs3806232: P= 0.009). Hence we found an important association between polymorphisms in the S100A8 gene and periodontitis in a Chinese population.