Recent experimental data have offered the biological background to study the estrogen receptor (ER) alpha gene as a candidate gene for AD. Genetic association studies proposed ERalpha PvuII and XbaI gene polymorphisms as susceptibility factors for AD, although subsequent studies did not replicate this finding. To verify this association in a Caucasian Italian sample, we conducted a case-control study in a dataset of 172 clinic-based probable AD cases and 172 age- and sex-matched controls. Possible interaction between ERalpha polymorphisms and sex, age at onset of AD or apolipoprotein E (APOE) was examined. The xx-genotype of the XbaI polymorphism was associated with the risk of developing AD in the total sample (OR 1.9, 95% CI [1.2-3.1]). The risk increased in women (OR 2.3, 95% CI [1.3-4.2]), and in subjects with late-onset AD (OR 2.1, 95% CI [1.2-3.5]). PvuII polymorphism did not contribute to the risk of AD. There was no evidence for a statistical interaction between the APOE and either the PvuII and XbaI polymorphisms. This result shows that ERalpha XbaI polymorphism is an additional risk factor for women with late-onset AD.