Non-alcoholic fatty liver disease (NAFLD) is now recognized as one of the most important causes of chronic liver disease in Western Countries, and is the hepatic manifestation of metabolic syndrome. The prevalence of NAFLD has increased with the global epidemic of obesity and type 2 diabetes mellitus. The pathophysiological hallmark of NAFLD is insulin resistance, associated with mediators of oxidative stress and inflammatory cytokines. Although simple steatosis by itself is generally benign, patients with histologically proven non-alcoholic steatohepatitis (NASH) can progress to cirrhosis. Hepatitis C (HCV) is another common cause of liver disease with some potential for progression to cirrhosis. Steatosis is present in almost 50% of patients infected by HCV. Hepatic steatosis in the setting of another liver disease (such as HCV) is associated liver disease progression. In particular, significant fibrosis is observed in patients with HCV whose liver biopsies show significant steatosis or superimposed NASH. This article reviews the host and viral factors potentially involved in the interaction between NAFLD and HCV. These factors include mediators of metabolic syndrome such as adipokines, inflammatory cytokines, factors associated with oxidative stress, lipid peroxidation products, as well as apoptosis and hepatic stellate cell activation with the resultant deposition of extracellular matrix. In addition to the mediators of metabolic syndrome (host factors), hepatic steatosis can be influenced by viral factors. The most important viral factor is HCV genotype 3, which has been independently associated with hepatic steatosis. Finally, superimposed NAFLD and visceral fat are associated with lower response rates to antiviral therapy in non-genotype 3 patients. Furthermore, viral clearance is associated with the resolution of hepatic steatosis in HCV genotype 3 but not other HCV genotypes. In these genotypes, hepatic steatosis and its impact on response to therapy are related to metabolic syndrome. Thus, the management of obesity and metabolic syndrome in patients with chronic hepatitis C may be important for reducing the risk of progression as well as improving the efficacy of antiviral therapy.