Our aim was to assess the use of peripheral blood mononuclear cells (PBMC) as an in vivo cellular model to evaluate diet-induced changes in the oxidative stress status by analysing the gene expression pattern of NADPH-oxidase subunits and antioxidant genes. A randomized, controlled trial assigned metabolic syndrome (MetS) patients to 4 diets for 12 weeks each: (i) high-saturated fatty acid (HSFA), (ii) high-monounsaturated fatty acid (HMUFA), and (iii) (iv) two low-fat, high-complex carbohydrate diets supplemented with n-3 polyunsaturated fatty acids (LFHCC n-3) or placebo (LFHCC). A fat challenge reflecting the same fatty acid composition as the original diets was conducted post-intervention. The mRNA levels of gp91phox (P<0.001), p22phox (P=0.005), p47phox (P=0.001) and p40phox (P<0.001) increased at 2 h after the intake of the HSFA meal. The expression levels of SOD1 SOD2, GSR, GPx1, GPX4, TXN, TXNRD1 and Nrf2 increased after the HSFA meal (p<0.05). In contrast, the expression of these genes remained unaltered in response to the other dietary interventions. Our results suggest that the increased expression of antioxidant genes in PBMC seems to be due to the response to the postprandial oxidative stress generated mainly in adipose tissue after the consumption of an HSFA diet.