Background: Epidemiological studies have suggested the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular health, but only limited data are available describing n-3 PUFA regulated pathways in humans. The aim of this study was to investigate the effects of n-3 PUFA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. Methods. Differentially expressed genes were detected after four hours, one week and twelve weeks of supplementation with either fish oil (FO) or corn oil in normo- and dyslipidemic men using whole genome microarrays. Results: Independent of the oil, a significantly higher number of genes was regulated in dyslipidemic subjects compared to normolipidemic subjects. Pathway analyses discovered metabolisms dominantly affected by FO after twelve weeks of supplementation, including the lipid metabolism, immune system and cardiovascular diseases. Several pro-inflammatory genes, in particular, were down-regulated in dyslipidemic subjects, indicating the immune-modulatory and anti-inflammatory capability of FO and its bioactive FAs, eicosapentaenoic acid and docosahexaenoic acid. Conclusions: This is the first study showing significant differences in gene expression profiles between normo- and dyslipidemic men after FO supplementation. Further studies need to clarify the exact role of n-3 PUFAs in pathways and metabolisms which were identified as being regulated after FO supplementation in this study. Trial registration. ClinicalTrials.gov (ID: NCT01089231).