A functional polymorphism in the coding region of brain-derived neurotrophic factor (BDNF) gene (196 A/G, Met66Val) has recently been reported to be associated with Alzheimer's disease (AD) and with an overrepresentation of G allele in AD patients, but different results have also been presented. We conducted a case-control study to analyze the association between the BDNF A/G polymorphism and sporadic AD in a sample composed of 203 AD patients and 239 controls from Mainland Chinese Han population. No association between the polymorphism and AD, no association between the polymorphism and age at onset in AD, and no significant interaction between BDNF and apolipoprotein E (APOE) genotype were detected in either the total or the male samples. However, a significantly high frequency of the GG genotype in the female controls compared with the female patients was detected. A postponed age at onset in the female patients with the GG genotype was also observed. These results suggest that the GG genotype has a protection effect from AD development in females. A significant low frequency of AD patients with the BDNF GG genotype in the AD APOEepsilon4 carriers compared with the frequency of the controls with the BDNF GG genotype in the control APOEepsilon4 carriers was also detected in the female individuals, suggesting that the BDNF GG genotype may reduce the effect of APOEepsilon4 on AD risk in females. Additionally, low frequencies of BDNF G allele and GG genotype were revealed in Chinese when compared with that in the other race populations so far reported.