Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity. (HEPATOLOGY 2010;51:1820-1832) P rimary liver cancer is one of the most common and deadly cancers worldwide. Globally, it represents the fifth most common cancer and the third most common cause of cancer death, behind only lung and stomach cancer. [1][2][3][4] Hepatocellular carcinoma (HCC) accounts for the majority of these primary cancers of the liver. More than 80% of HCC cases occur in less developed countries, particularly East Asia and sub-Saharan Africa, and are typically associated with chronic hepatitis B and C, although the incidence in these countries is decreasing. 3,4 Interestingly, the incidence of HCC in developed countries including Japan, Australia, Europe, Canada, and the United States has been increasing over the last 20 years. 5,6 In the United States alone, the annual incidence of HCC has increased about 80% during the last 2 decades. 1 The emergence of hepatitis C virus (HCV) in developed countries accounts for about half of this increase in HCC. 1,6 The etiology of HCC in 15%-50% of new HCC cases remains unclear, which suggests that other risk factors likely account for the increase. 7 The most common form of chronic liver disease in these developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease, which can progress to cirrhosis and its associated Abbreviations: BMI, body mass index; CC, cryptogenic cirrhosis; HBV,