The response of plasma cholesterol to diet is modulated by endogenous and exogenous factors such as body mass, tobacco consumption, gender and the genetic background. Our purpose was to know whether the response degree depends on the concentration of cholesterol prior to the intervention and whether several polymorphisms modulating the cholesterol response to diet are actually involved in such response.Seventy two males with hypercholesterolemia were administered three different 4-weeks duration diets. The first one was a saturated fat-enriched (SAT) diet. Then, in a randomized and crossed manner, subjects were categorized in two groups: one group received a diet with low fat but high complex carbohydrates contents (HCO); the another group received a monounsaturated fat-enriched diet (Mediterranean diet). In the third period, we inverted the diets of the previous period. We determined the prevalent genotypes of the following apoproteins: E, CIII, A-IV, A-I, B, A-IV 360.The diet with low fat contents and the Mediterranean diet led to a significant decrease of total cholesterol, LDL-c and HDL-c. Those at the upper LDL-c tertile, after the SAT diet, were found to have statistically significant greater decreases (absolute and relative values) with the Mediterranean and HCO diet. In the multivariate analysis, the only variable with an effect on the modification of LDL-c, after shifting a SAT to any hypolipidemic diet, were the levels of LDL-c at the end of a SAT diet. The allelic frequency of different apoproteins in the hyper-respondent group was not different from that in the hypo-respondent group (response displayed when going from a SAT period to any hypolipidemic diet).The decrease of LDL-c observed with hypolipidemic diets (low in fat contents or Mediterranean) was more significant in those individuals with hypercholesterolemia who had higher levels of LDL-c at the onset.