Background – A significant part of vitamin D present in the human body is synthesized in the skin following UV light exposition. However, to obtain or maintain an adequate vitamin D status, most individuals have to consume vitamin D, either as part of their diet or as supplements. The blood response to vitamin D supplementation has been shown to exhibit a large interindividual variability. Moreover, vitamin D intestinal transport depends, at least partly, on proteins and we have shown that the bioavailability of other lipid micronutrients (tocopherol, lutein, lycopene and beta-carotene), which share common absorption mechanism with cholecalciferol (D3),was partly modulated by single nucleotide polymorphisms (SNPs) in genes involved in the intestinal transport of these micronutrients and in the metabolism of chylomicrons. The main objective of this study was thus to identify SNPs associated with the interindividual variability in the bioavailability of D3. Methods – Thirty nine healthy adult men were genotyped using whole-genome microarrays. They consumed a meal that contained 5g D3 as a supplement. D3 and calcifediol (25(OH)D) concentration in plasma chylomicrons was measured at regular time intervals up to 8h after meal intake. The association between SNPs in genes involved in vitamin D and lipid metabolism (61 candidate genes representing 3791 SNPs) and the D3 response (calculated as the area-under-the-curve of the postprandial chylomicron D3 concentration) was analysed by partial least squares regression (PLS regression). Results – The postprandial chylomicron D3 concentration peaked 5.4 h after meal intake. There was no significant variation in the postprandial chylomicron 25(OH)D concentration. The D3 response displayed a large interindividual variability (CV=47%). It correlated positively with the postprandial chylomicron triglyceride response (r=0.60, P<0.001) but not with the fasting 25(OH) D plasma concentration (a marker of vitamin D status) (r=0.04, P=0.83). A significant (P=1.32x10-4) PLS regression model, which included 17 SNPs in 13 genes (LPL, ISX, SLC10A2, GC, SCARB1, PNLIP, DHCR7, ABCA1, ABCB1, APOB, MAPRE2, BET1, NAT2), was associated with the variance in the D3 response. Five of these genes (ABCA1, APOB, BET1, LPL and NAT2) have been associated in another study with the postprandial chylomicron triglyceride response in the same subjects. Conclusions – In a group of healthy men, we observed a high interindividual variability in D3 bioavailability which was associated with a combination of SNPs located in/near genes involved in both vitamin D and lipid metabolism. Desmarchelier et al., A Combination of Single-Nucleotide Polymorphisms Is Associated with Interindividual Variability in Cholecalciferol Bioavailability in Healthy Men, Journal of Nutrition, In Press.