The feeding of cholesterol-rich diets to random-bred animals results in marked interindividual differences in the response of serum cholesterol. Certain animals show only small responses (hyporesponders), whereas others develop high degrees of hypercholesterolemia (hyperresponders). Inbred strains of rabbits, rats, and mice differing in their sensitivity to dietary cholesterol are available. In these animals, and also in monkeys, the responsiveness to high-cholesterol diets has a strong genetic basis. The existence of hyper- and hyporesponders also holds in humans, though not as pronounced as in laboratory animals. Repeated trials with the same subjects have shown that persons exist with a consistently low or high response to increased intakes of cholesterol. However, "spontaneous," diet-independent within-person variations in the level of serum cholesterol markedly inflate the between-person variation in the response of serum cholesterol; both variations are of the same order of magnitude. Hypo- and hyperresponsiveness to dietary cholesterol extends to other hypercholesterolemic components of the diet. In humans and rabbits hyperresponsiveness to dietary cholesterol is associated with responsiveness to dietary saturated fatty acids. The mechanisms underlying hypo- and hyperresponsiveness to dietary cholesterol have not yet been unraveled. On the basis of available data, we propose that in hyperresponders, compared with hyporesponders, there is a higher hepatic efflux of cholesterol in low-density lipoproteins (LDL), or its precursors, after cholesterol consumption. This may be caused by insufficient inhibition of cholesterol biosynthesis and/or the high capacity of cholesterol absorption in the hyperresponders. The stimulation of LDL production accounts for the increase in LDL cholesterol in serum. The number of hepatic LDL receptors, which may be already decreased in hyperresponders, will decrease further through down-regulation. The receptor-mediated LDL clearance decreases, but the absolute amount of LDL cholesterol taken up by the cells via the receptor and by the receptor-independent pathway increases because of the increased level of LDL cholesterol. In this way a new equilibrium is reached in which LDL production equals LDL catabolism. The phenomenon of hypo- and hyperresponsiveness may have implications for counseling subjects who attempt to lower their serum cholesterol by diet. However, identification of true hyper- and hyporesponders is greatly hampered by within-person fluctuations of the level of serum cholesterol. No simple test is available to discriminate hypo- from hyperresponders.(ABSTRACT TRUNCATED AT 400 WORDS)