Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant (POP) with worldwide bioaccumulation due to a very long half-life. PFOS exposure results in significant hepatic effects including steatosis, proliferation, hepatomegaly and in rodents, carcinogenesis. The objective of this study was to determine if PFOS exposure exacerbates nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) pathogenesis. Eight-week-old male C57BL/6J mice (n=5 per group) were fed ad libitum either normal chow diet (ND) alone, 60% high fat diet (HFD) alone, ND+PFOS and HFD+PFOS (0.0001% w/w (1mg/kg) of PFOS) for 6 weeks. Both HFD alone and the ND+PFOS treatment induced significant adiposity and hepatomegaly, but the HFD+PFOS treatment showed a marked protection. Oil Red O staining and quantitative analysis of hepatic lipid content revealed increased hepatic steatosis in ND+PFOS and in HFD alone fed mice, which was prevented in HFD+PFOS treatment. Further studies revealed that ND+PFOS treatment significantly affected expression of lipid trafficking genes to favor steatosis but these changes were absent in HFD+PFOS group. Specifically, expression of CD36, the major lipid importer in the cells, and PPARγ, its major regulator, were induced in HFD+NT and ND+PFOS-fed mice but remained unchanged in HFD+PFOS mice. In conclusion, these data indicate that co-administration of PFOS with HFD mitigates steatosis and hepatomegaly induced by HFD and that by PFOS fed in ND diet via regulation of cellular lipid import machinery. These findings suggest dietary lipid content be considered when performing risk management of PFOS in humans and the elucidation of PFOS induced hepatotoxicity.