Scope Phytofluene is a colorless carotenoid with potential health benefits that displays a higher bioavailability compared to carotenoids such as lutein, β‐carotene or lycopene. Several studies suggest its bioavailability displays an elevated interindividual variability. The aim of this work is to investigate whether a combination of SNPs is associated with this variability. Methods and Results Thirty‐seven healthy adult males consume a test meal that provides phytofluene from a tomato puree. Phytofluene concentrations are measured at fast and in chylomicrons at regular time intervals after meal intake. Identification of the combination of SNPs that best explained the interindividual variability of the phytofluene response is assessed by partial least squares regression. There is a large interindividual variability in the phytofluene response, with CV = 88%. Phytofluene bioavailability is positively correlated with fasting plasma phytofluene concentration ( r = 0.57; p = 2 × 10 −4 ). A robust partial least squares regression model comprising 14 SNPs near or within 11 genes ( ABCA1 ‐rs2487059, rs2515629, and rs4149316, APOC1 ‐rs445925, CD36 ‐rs3211881, ELOVL5 ‐rs6941533, FABP1 ‐rs10185660, FADS3 ‐rs1000778, ISX ‐rs130461, and rs17748559, LIPC ‐rs17240713, LPL ‐rs7005359, LYPLAL1 ‐rs1351472, SETD7 ‐rs11936429) explains 51% (adjusted R 2 ) of the interindividual variability in phytofluene bioavailability. Conclusions This study reports a combination of SNPs that is associated with a significant part of the interindividual variability of phytofluene bioavailability in a healthy male adult population.