There is increasing evidence suggesting the importance of evaluating gene-environment interactions in the genetic study of coronary artery disease (CAD). We investigated the association of multiple single nucleotide polymorphisms in the angiotensinogen (AGT) gene with CAD, considering the interaction between the genetic and non-genetic factors, using a larger and ethnically homogeneous angiographic cohort. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with CAD and 519 without) were recruited. T174M (rs4762), M235T (rs699), G-6A, A-20C, G-152A, and G-217A polymorphisms of the AGT gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects defined by the multilocus data and detection of gene-environment interaction by incorporating interaction terms in the model. We found significant differences in global AGT gene haplotype profile between patients with and without CAD (the global score statistic=25.411, P=0.008). Significant interactions between AGT gene haplotypes, gender and hypertension were detected. We also used haplotype counting to directly estimate the odds ratio of each AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups defined by gender and hypertension, providing strong evidence of gene-environment interaction. Female gender synergistically enhances (or male gender reverses) the effects of AGT gene haplotypes on the risk of CAD in the presence of hypertension. In conclusion, the effect of AGT gene haplotypes on the risk of CAD was significantly increased in women with hypertension, which highlights the importance of evaluating gene-environment interactions in the genetic study of CAD.