Abstract: AIM To investigate the possible association between polymorphisms of SCN5A gene and sick sinus syndrome(SSS) in Han population in South China. METHODS A case-control design was applied in this study. A total of 108 unrelated hospitalized patients suffering from SSS were enrolled from Nafang Hospital between October 2006 and December 2007. One hundred and twenty-three control subjects were recruited from individuals participating in a community-based survey in Guangzhou area. One SNPs of SCN5A gene D1819D was genotyped by restriction fragment length polymorphism (RFLP) in all the subjects. Univariate analysis was applied to examine the association of single polymorphism with SSS and binary logistic regression was performed to investigate the independent effect between the gene type of the polymorphisms and SSS. RESULTS No significant difference was found in the age and the gender between SSS subjects and normal control (t=0.814, P>0.05; P=0.246, P>0.05, respectively). The frequencies of genotype of CC, CT and TT were respectively 24, 48, 36 in SSS subjects, and 48, 45, 30 in normal control, which were all in good agreement with Hardy-Weinberg equilibrium. There was a significant difference in the distributions of the genotypes (CC, CT, TT) between SSS subjects and normal control (χ2=7.701, P=0.021). In addition, significant difference was also observed in D1819D allele frequency between the two groups (χ2=7.628, P=0.006). Among Han population in Southern China, the minor allele frequency of D1819D was 0.427. The presence of C allele of D1819D gene was found to be a greater protective factor in normal control than in SSS subjects. The odds radio (OR) of CC was 0.417 (0.209-0.830), when compared with that of TT genotype, the P=0.03 (P<0.05). CONCLUSION The study suggests that existence of D1819D polymorphisms of SCN5A gene may be related to SSS in Han Nationality in South China. For SSS, C allele may be a protective gene, while T allele may be a susceptibility gene.