We investigated the association of five intronic single-nucleotide polymorphism (SNP) at the estrogen receptor beta (ESR2) gene locus and the susceptibility of developing Alzheimer's disease (AD) in 387 subjects with clinically diagnosed probable AD and 467 cognitively normal individuals derived from eastern Finland. According to our results, variation in the ESR2 gene is associated with an increased risk of AD in women, whereas it does not contribute to the disease susceptibility in men. More specifically, in women, the allele T and the genotype T/T of two of the studied ESR2 gene SNPs (SNP2 and SNP3) were more frequent in AD women than in cognitively normal control women (P=0.012 and P=0.016, respectively). The ESR2 SNP2 T/T genotype and the SNP3 T/T genotype were associated with a significant, nearly two-fold increase in the risk of AD in women (OR=1.87, 95% CI=1.21-2.90), and remained significant after adjustment with the APOE genotype and age (OR=1.63, 95% CI, 1.00-1.68). The combined effect of the ESR2 SNP2 T/T or SNP3 T/T genotype and female gender increases the risk of the disease (OR=3.2, 95% CI=1.3-7.7). Consistent with these results, also the frequency of the haplotype containing the two above ESR2 gene risk alleles was elevated in AD women (P=0.027, OR=1.3, 95% CI=1.02-1.65). Results show that variation in ESR2 gene may be linked with increased AD susceptibility and furthermore, this association is gender specific.