The aim of the present study was to investigate whether the cholesteryl ester transfer protein (CETP) I405V polymorphism modifies the response to changes in the dietary ratio of polyunsaturated to saturated fat (P:S). The population included 85 healthy subjects with the different I405V genotypes (35 II, 36 IV, and 14 VV) assigned to two consecutive 28-day experimental period. All subjects consumed a high-P:S with P:S of 1.2 for the first period and a low-P:S with a P:S of 0.3 for the next 28-day period. At the first and end of each dietary period, serum lipid, lipoprotein, and CETP concentrations were measured. At screening, lipid or lipoprotein concentrations were not significantly different among CETP I405V genotype groups. After the low-P:S diet, subjects carrying V allele had greater reduction in apoA-I and HDL cholesterol (HDL-C) than subjects with II genotype. A genotype-by-diet interaction effect was observed on apoA-I (p=0.016) concentrations. In conclusion, the CETP I405V polymorphism contributes to the unfavorable changes of apoA-I and HDL-C when a high-P:S diet was replaced with a low-P:S diet.