Previous studies on the effects of genetic polymorphisms on the serum cholesterol response to dietary treatments were often inconsistent and frequently involved small numbers of subjects. We studied the effect of 10 genetic polymorphisms on the responses of serum cholesterol to saturated and trans fat, cholesterol and the coffee diterpene, cafestol, as measured in 26 dietary trials performed over 20 years in 405 mostly normolipidaemic subjects. Apoprotein A4 360-2 allele attenuated the response of low-density lipoprotein cholesterol to dietary cholesterol, but not in women. Subjects with the cholesteryl ester transfer protein TaqIb-1 allele had 0?02 to 0?05 mmol L1 smaller responses of high-density lipoprotein cholesterol to diet than those with the 2/2 genotype. The effects of the other eight polymorphisms on cholesterol response were either inconsistent with results in previous studies or need to be replicated in other studies. Apoprotein A4360 and cholesteryl ester transfer protein TaqIb polymorphisms may affect dietary responses. However, no one single genotype was a major determinant of a subject's lipid response to diet. Therefore, knowledge of these genotypes by themselves is of little use in the identification of subjects who may or may not benefit from dietary treatment.