Previous studies on the effect of apoprotein E (APOE) polymorphism on the response of serum lipids to diet showed inconsistent results. We therefore studied the effect of apoprotein E polymorphism on responses of serum cholesterol and lipoproteins to various dietary treatments. We combined data on responses of serum cholesterol and lipoproteins to saturated fat, to trans-fat, to dietary cholesterol, and to the coffee diterpene cafestol with newly obtained data on the apoprotein E polymorphism in 395 mostly normolipidemic subjects. The responses of low-density lipoprotein (LDL-) cholesterol to saturated fat were 0.08 mmol/l larger in subjects with the APOE3/4 or E4/4 genotype than in those with the APOE3/3 genotype (95% confidence interval: −0.01–0.18 mmol/l). In contrast, responses of LDL-cholesterol to cafestol were 0.11 mmol/l smaller in subjects with the APOE3/4 or E4/4 genotype than in those with the APOE3/3 genotype (95% confidence interval: −0.29–0.07 mmol/l). Responses to dietary cholesterol and trans-fat did not differ between subjects with the various APOE genotypes. In conclusion, the APOE genotype may affect the response of serum cholesterol to dietary saturated fat and cafestol in opposite directions. However, the effects are small. Therefore, knowledge of the APOE genotype by itself may be of little use in the identification of subjects who respond to diet.