Alzheimer disease (AD) is a polygenic multifactorial disorder. Several studies suggested that the neuroprotective effect of estrogen was based on an APOE-dependent mechanism. The goals of the current study were to determine if the genes involved in estrogen metabolism were linked to the risk of AD and find out if there was an interaction between estrogen-metabolizing gene polymorphisms and the APOE Ε4 allele in the risk of prevalent AD. We investigated 66 patients with AD and 86 age- and gender-matched normal subjects. The polymorphisms of APOE and estrogen-metabolizing genes CYP17, CYP1A1 and COMT were examined. No association was found between each estrogen-metabolizing gene polymorphism and AD. However, the COMT HH genotype and APOE Ε4 allele had a synergistic effect on the risk of AD. Taking subjects with Ε4–Ε4–/HH– as reference, the risk of developing AD in subjects with one Ε4 allele (Ε4+Ε4–/HH–) was 2.6 (95% confidence interval, CI, 0.7– 9.1); however, the risk in subjects with both HH and one Ε4 (Ε4+Ε4–/HH+) increased to 3.6 (95% CI 1.2–10.6). The subjects with homozygous Ε4 still had the highest risk in developing AD (odds ratio 6.6, 95% CI 0.6–69.6). The p value of the linear trend test for this regression model was 0.004. It is possible that a high metabolism of estrogen by COMT may have reduced the protective effect of estrogen in AD. Further studies to clarify this interaction may improve our understanding of the generic risks for AD.