Hormone therapy increases the risk of venous thromboembolism (VTE) among postmenopausal women. This effect may be modulated by the expression of cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) which are involved in the hepatic metabolism of estrogens. The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy. We conducted a case-control study. This study was conducted in eight French hospital centers and in the general population. CYP3A5 and CYP1A2 genotypes were evaluated among 195 cases with a first documented episode of idiopathic VTE and 533 controls matched for center, age, and admission date. The outcome measure was hormone therapy by route of estrogen administration. Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6-7.6, and OR = 1.2, 95% CI = 0.8-1.8, respectively]. The allele frequency of CYP3A5*1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6-1.5) and that of CYP1A2*1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8-2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1-6.7) among patients without CYP3A5*1 allele and 30.0 (95% CI = 4.4-202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk. Women with CYP3A5*1 allele using oral estrogen can define a subgroup at high VTE risk. Additional data are needed to assess the relevance of this genetic biomarker in the medical management of menopause.