Evidences suggest that omega-3 fatty acid (n-3 PUFA) metabolism is imbalanced in apolipoprotein E epsilon 4 isoform carriers (APOE4). This study aimed to investigate APOE genotype-dependant modulation of FA profiles, protein and enzyme important to fatty acid (FA) metabolism in the adipose tissue, the liver and the plasma using human APOE-targeted replacement mouse-model (N=37). FA transport (FATP) and binding (FABP) protein levels in tissues and concentrations of liver carnitine palmitoyltransferase 1 (CPT1) were performed. N-3 PUFA concentration was >45% lower in the adipose tissue and liver of APOE4 mice compared to APOE3 mice. In APOE4 mice, there were higher levels of FATP and FABP in the liver and higher FATP in the adipose tissue compared to APOE2 mice. There was a trend towards higher CPT1 concentrations in APOE4 mice compared to APOE3 mice. Therefore, since APOE-isoform differences were not always in line with the unbalanced n-3 PUFA profiles in organs, other proteins may be involved in maintaining n-3 PUFA homeostasis in mice with different APOE-isoforms.