Objective: To investigate the association of the single nucleotide polymorphisms (SNPs) G→A (R219K) in the exon 6 of ATP-binding cassette transporter Al (ABCA1) gene with sporadic Alzheimer's disease (SAD) in the Han Chinese population. Methods: Genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) in 168 SAD patients and 215 healthy controls. The association between the polymorphism and AD was estimated with the odds ratios (OR). Results: The frequency of A allele in SAD cases was significantly lower than in controls (37.8% vs 48.1%, x 2 = 8.204, P = 0.004), and the frequency of AA genotype in SAD cases was also significantly lower than in control (14.3% vs 22.8%, x 2 = 8.230, P= 0.016). Logistic regression analyses adjusted for age, gender and ApoEε4 status showed that the risk for AD was decreased in A allele (G/A + A/A genotypes, OR 0.57, 95% CI 0.36-0.91, P = 0.019) or AA homozygote carriers (OR 0.40, 95% CI 0.21-0.11, P = 0.006) compared with GG genotypes carriers. Conclusion: Our data indicate a genetic association between polymorphism in exon 6 of ABCA1 gene and the risk of AD and reveal that AA genotype or A allele of ABCA1 gene may have a protective effect on AD in the Han Chinese.