Fish oil supplementation is generally seen as beneficial for human health, due to the presence of n-3 polyunsaturated fatty acids (n-3 PUFAs). These fatty acids can elicit their effect through changes in gene expression. Effects of n-3 PUFAs on gene expression of inflammatory and atherogenic markers have been shown in several in vitro and animal studies. However, little evidence is available on human in vivo studies on n-3 PUFA related gene expression. In the present study we investigate the effects of EPA and DHA supplementation for 6 months on gene expression profiles of peripheral blood mononuclear cells (PBMCs). Whole genome microarray analysis was performed on PBMC RNA from subjects who received 1.8 grams of EPA and DHA in capsules (n=23) or capsules containing high oleic acid sunflower oil (HOSF)(n=25). Intake of EPA and DHA resulted in a change of 1040 genes. We found a down-regulation in inflammatory and atherogenic related pathways, such as NF-κB signaling, eicosanoid synthesis, scavenger receptors activity and cell adhesion. These results seem to point to an improvement in health status, in which lymphocytes are less prone to produce chemokines and adhesion molecules and monocytes show reduced susceptibility to differentiate into foam cells. Overall, beneficial effects of n-3 PUFAs that have been described in vitro and in animal studies, were shown in vivo in human subjects in this study. This not only confirms that EPA and DHA elicits beneficial effects on inflammatory and atherogenic processes of elderly subjects, but also shows that PBMC gene expression profiles can be used to show effects of nutrition on human health status.