||The present study was conducted on CD4+ Tcells, isolated fromwild type (WT) and PPARαnull mice, in order to assess the mechanism of action of do-cosahexaenoic acid (DHA), an n-3 fatty acid, in the modulation of two tran-scription factors, i.e., T-bet and GATA-3, implicated in T-cell differentiation towards, respectively, TH1 and TH2 phenotype. The T-cells from P PPARαnull mice secreted higher IFN-γ and lower IL-4 concentrations than WT T-cells. Furthermore, the deletion of PPARa gene in T-cells resulted in the upregulation of T-bet and downregulation of GATA-3 both at mRNA and protein levels. DHA exerted not only an inhibitory effect on T-cell pro-liferation, but also diminished IFN-γ and stimulated IL-4 secretions in both cell types. DHA also downregulated T-bet and u regulated GATA-3 both at transcription and protein levels. Though the T-cells from PPARαnull mice ex-pressed higher p38 phosphorylation than WT T-cells, DHA diminished the MAP kinase phosphorylation (p38 and ERK1/2) in both the cell types. The pharmacological inhibitors of MAP kinases also downregulated T-bet and upregulated GATA-3 in T-cells. Altogether, these results demonstrate that DHA, via its action on MAP kinases, modulates the expression of transcrip-tion factors. These results also explain the mechanism of action of this fatty acid on T-cell differentiation in disease and health.