PPARgamma is a transcriptional regulator of metabolism; its activity can be modulated by direct binding of dietary lipids. The most prevalent human PPARgamma gene variant, Ala12, is associated with postprandial hypertriglyceridemia in patients with metabolic syndrome, although the mechanism whereby this polymorphism affects lipid homeostasis remains to be fully determined. Using peripheral blood mononuclear cells (PBMC), we studied the effect of the Pro12 and Ala12 polymorphisms on mRNA expression of PPARgamma and nuclear factor kappa B genes before and 3 and 4 h after fat overload. We also studied several biochemical and oxidative stress variables. Most of the indicators of oxidative stress were higher in patients with metabolic syndrome than in healthy subjects before and after fat overload. Patients also differed depending on whether they had the Pro12 or Ala12 variant in PBMC; PPARgamma expression was lower in healthy subjects compared with patients. After fat overload, circulating triglycerides and PPARgamma expression were positively correlated (r = 0.617, P < 0.05), and PPARgamma expression tended to be negatively correlated with 2 important markers of oxidative stress: plasma lipid peroxidation (r = -0.224, P < 0.1) and carbonylated proteins (CPro) (r = -0.340, P < 0.1) concentrations. We also found differences in several indicators of oxidative stress between Pro12 and Ala12 patients, including an increase in plasma CPro before and after fat overload in Ala12 but not Pro12 patients. These data provide evidence that the Ala12 sequence variant is associated with a worse metabolic profile than Pro12. This is related to differences in the expression of PPARgamma and to oxidative imbalance after fat overload.