Scope Cholesterol bioavailability displays a high interindividual variability, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explained a minor fraction of the variability of this complex phenotype. The aim is to identify a combination of SNPs associated with a significant part of the variability in cholesterol bioavailability. Methods and results Thirty-nine healthy adult males are given a standard test snack containing 80 mg heptadeuterated (D7) cholesterol. The plasma D7-cholesterol concentration is measured at equilibrium 40 h after test snack intake. The D7-cholesterol response (D7-cholesterol/total cholesterol concentration) exhibits a relatively high interindividual variability (CV = 32%). The association of exonic SNPs in candidate genes (188 genes involved in or related to cholesterol metabolism) with the plasma D7-cholesterol response is assessed by univariate statistics followed by partial least squares regression. A significant model (p-value after cross-validation ANOVA = 1.64 x 10(-7)) that includes 8 SNPs (SOAT2-rs9658625,DNAH11-rs11768670,LIPC-rs690,MVK-rs2287218,GPAM-rs10787428,APOE-rs7412,CBS-rs234706, andWRN-rs1801196) explains 59.7% of the variance in cholesterol bioavailability (adjustedR(2)). Conclusion Here a combination of SNPs is significantly associated with the variability in dietary cholesterol bioavailability in healthy adult males.