Purpose: The enzymes encoded by fatty acid desaturases (FADS) genes determine the desaturation of long-chain polyunsaturated fatty acids (LCPUFA). We investigated if haplotype and single nucleotide polymorphisms (SNPs) in FADS gene cluster can influence LCPUFA status in infants who received either fish oil or placebo supplementation. Methods: Children enrolled in the Infant Fish Oil Supplementation Study (IFOS) were randomly allocated to receive either fish oil or placebo from birth to 6 months of age. Blood was collected at 6 months of age for the measurement of fatty acids and for DNA extraction. A total of 276 participant DNA samples underwent genotyping, and 126 erythrocyte and 133 plasma fatty acid measurements were available for analysis. Twenty-two FADS SNPs were selected on the basis of literature and linkage disequilibrium patterns identified from the HapMap data. Haplotype construction was completed using PHASE. Results: For participants allocated to the fish oil group who had two copies of the FADS1 haplotype consisting of SNP minor alleles, DHA levels were significantly higher compared to other haplotypes. This finding was not observed for the placebo group. Furthermore, for members of the fish oil group only, the minor homozygous carriers of all the FADS1 SNPs investigated had significantly higher DHA than other genotypes (rs174545, rs174546, rs174548, rs174553, rs174556, rs174537, rs174448, and rs174455). Conclusions: Overall results of this preliminary study suggest that supplementation with fish oil may only significantly increase DHA in minor allele carriers of FADS1 SNPs. Further research is required to confirm this novel finding.