BACKGROUND AND AIM: Plasma high density lipoprotein cholesterol (HDL-C) levels are determined by a variety of environmental and genetic factors. The cholesteryl ester transfer protein (CETP) and apolipoprotein A-I (Apo A-I) are considered to be associated with HDL-C metabolism. The aim of this study was to investigate the relationship between the CETP gene Taq I B and Apo A-I gene Msp I polymorphisms and plasma lipid levels taking into account environmental factors, and to determine the combined effects of these polymorphisms on HDL-C levels in Japanese women. METHODS AND RESULTS: The study involved 270 Japanese women aged 30-69 years. We found a significant association between the CETP genotypes and HDL-C levels (p=0.0020), which were also associated with the Apo A-I gene (M1) polymorphism. Stepwise multiple regression analysis revealed that both the CETP Taq I B and Apo A-I gene (M1) genotypes were independent predictive variables. The strength of the association between the Apo A-I (M1) subgroup and HDL-C levels was reduced in the subjects with a high Body Mass Index (BMI). The combination of genotypes provided more detailed information about HDL-C levels. The "high risk" combination of the M1+ (M1+/+) and B1B1 genotypes was associated with the lowest HDL-C level (1.52+/-0.36 mmol/L), and the "low risk" combination of the M1- (M1+/- or M1-/-) and B2B2 genotypes was associated with the highest HDL-C levels (2.06+/-0.34 mmol/L). CONCLUSIONS: Our results suggest that the combination of the two polymorphisms influences HDL-C levels in women, and that the association between genetic factors and HDL-C levels is altered by environmental factors. They may also help to detect individuals with low HDL-C levels at high risk for coronary artery syndrome.