The intake of soy protein has been associated with improvements in lipid metabolism, with much attention being focused on the serum cholesterol-lowering property of soy. The component or components of soy that are responsible for improvements in lipid metabolism have been investigated and their specific actions debated. One component, the isoflavones, have been shown to have weak estrogenic activity, and recently, several research groups have suggested that isoflavones are activating peroxisome proliferator activated receptors (PPARs). The three different isoforms of PPARs (, , and ) have overlapping tissue distributions and functions associated with lipid metabolism. The goal of the present study was to investigate the hypothesis that the effect of isoflavones are mediated through the PPAR receptor. Male and female 129/Sv mice were obtained, including both wild type and genetically altered PPAR knockout mice. Groups of mice were fed high-fat atherogenic diets containing soy protein +/- isoflavones and PPAR agonist fenofibrate for 6 weeks. At the end of 6 weeks, serum and tissue lipid levels were measured along with hepatic gene expression. Most notably, serum triglycerides were reduced by isoflavone consumption. Compared with intake of a low-isoflavone basal diet, isoflavone intake reduced serum triglyceride levels by 36% and 52% in female and male wild type mice, respectively, compared to 55% and 52% in fenofibrate-treated mice. Isoflavones also improved serum triglyceride levels in knockout mice while fenofibrate did not, suggesting that two different regulatory mechanisms may be affected by isoflavone intake. Isoflavone intake resembled action of fenofibrate on PPAR-regulated gene expression, although less robustly compared to fenofibrate. We suggest that at the levels consumed in this study, isoflavone intake is altering lipid metabolism in a manner consistent with activation of PPAR and also via a PPAR-independent mechanism as well.