Lipodystrophies are acquired and genetic disorders characterized by the complete or partial absence of body fat with a line of metabolic disorders, including hepatic steatosis. Because soy protein isolate (SPI) has been reported to reduce cholesterol and triglyceride levels in animals and humans, we explored the effect of SPI on the pathophysiology of hepatic lipid accumutaion in a diet-induced lipodystrophy model mice. Four weeks of the lipodystrophy model diet induced hepatic lipid accumulation concomitant with marked deficiencies of adipose tissue and serum adipocytokines in mice. However, supplementing the lipodystrophy model diet with SPI could alleviate the hepatic lipid acculation without affecting the lipoatrophic effect of the diet. Enhanced lipogenesis is the principal mechanism of hepatic steatosis in this model, but SPI supplementation significantly attenuated the increase in enzyme activity and/or mRNA expression. Additionally, SPI supplementation upregulated the hepatic mRNA expression of an enzyme involved in cholesterol catabolism. In conclusion, our results indicate the possibility of dietary SPI to attenuate lipodystorophy-induced hepatic steatosis through the direct reduction of hepatic lipogenesis without affecting adipocytokine production.