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Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of the cell. This imbalance and an excess of ROS induce tissue/cellular damage, which are implicated in chronic inflammation disorders such as obesity, insulin resistance, and metabolic syndromes. Peroxiredoxins (Prxs) are the most abundant and ancient cellular antioxidant proteins that help to control intracellular peroxide levels and ROS-dependent signaling. Of the six mammalian isoforms, Prx III is specifically localized in mitochondria. In this study, we detected novel associations between genetic variations of the PRDX3 gene and BMI and obesity risk in the general Japanese population. In addition, these associations were observed only in the subjects with high dietary fat intake, but not in the subjects with low dietary fat intake. These findings indicate that the interaction between genetic variations in the PRDX3 gene and dietary fat intake is important for modulation of BMI and obesity risk.