Background and objectives: Atherosclerosis results from a complex interaction between genetic and environmental factors. Free cholesterol efflux from peripheral tissues and transferring to the liver for excretion from bile which is known as reverse cholesterol transfer (RCT) plays a central role in protection against atherosclerosis. HDL and cholesteryl ester transfer protein (CETP) are the major participants of RCT. The aim of the present study was to investigate whether the cholesteryl ester transfer protein I405V polymorphism modifies the response to changes in the dietary ratio of polyunsaturated to saturated fat (P:S). Materials and Methods: The population study included 85 healthy subjects with the different I405V genotypes (35 II, 36 IV, and 14 VV) who assigned to two consecutive 28 days experimental period. All subjects consumed a high polyunsaturated fatty acids (PUFA) diet with P:S of 1.2 for the first period and a high saturated fatty acids (SFA) diet with a P:S of 0.3 for the next 28 days period. At the first and the end of each dietary period, serum lipid and lipoprotein concentrations were measured. Results: At beginning of screening, lipid or lipoprotein concentrations were not significantly different among CETP I405V genotype groups. After the high SFA diet, subjects carrying V allele had a greater reduction in apolipoprotein A-I (apoA-I) and HDL cholesterol (HDL-C) than subjects with II genotype. Conclusion: The CETP I405V polymorphism contributes to the unfavorable changes of apoA- I and HDL-C when a high PUFA diet were replaced with a high SFA diet.