Although soy foods are recommended to prevent hyperlipidemia and related diseases, it is unclear how their active ingredients exert their effects. Here, the effects of tofu (soybean curd) and its putative active components, protein and isoflavone, on lipid metabolism in male rats were compared. Tofu and soy protein significantly lowered serum triacylglycerol and cholesterol levels compared to casein and, through microarray analyses, were found to exclusively alter transcriptomes involved in fatty acid and/or steroid synthesis in the liver, where most of the serum lipids are synthesized. In contrast, isoflavone supplementation had little effect on serum lipid levels or gene expression and exerted no synergistic effects with soy protein or tofu. The importance of the proteinaceous components was further confirmed by the lower activity of enzymes involved in lipogenesis. From these findings it was concluded that the protein, not isoflavone, fraction of soy reduces lipogenesis in liver through gene expression and that this may result in lower serum lipid levels.