Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual's response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (-13%) and glucose (-11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual's response to fish oil supplements.