Statins can modestly raise the levels of HDL cholesterol and apolipoprotein A-I (APOA1). Recently, associations between polymorphisms in the estrogen receptor alpha (ESR1) and the HDL cholesterol response to hormone replacement therapy were reported. To test the hypothesis that common polymorphisms in ESR1 and APOA1 genes are associated with the response to statin therapy, two ESR1 (PvuII and XbaI) and two APOA1 (G-75A and +83) polymorphisms were examined in 338 hypercholesterolemic patients treated with atorvastatin 10mg. The ESR1 PvuII-XbaI+ haplotype was significantly, and independently, associated with a greater response of HDL raising in women (+13% versus +7%, p=0.010) but not in men (+9% versus +7%, p=0.248). Effects of the APOA1+83 variant allele on HDL cholesterol response also differed significantly by gender (p=0.012). The APOA1+83 variant allele was associated with higher basal LDL cholesterol levels in men as well, but not in women. Finally, significant interactions were observed between the ESR1 PvuII-XbaI+ haplotype and the APOA1+83 variant allele regarding both HDL (p=0.042) and LDL (p=0.031) cholesterol responses. In conclusion, the ESR1 haplotype was associated with a greater HDL-raising to atorvastatin in a gender-specific manner, and the interactions between ESR1 and APOA1 genotypes regarding HDL and LDL cholesterol response were also gender specific.