Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, !18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 3 upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 3 ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 3 ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P 5 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P 5 0.033). Conclusions: A SF >1.5 3 ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis. (HEPATOLOGY 2012;55:77-85) N onalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of liver disease and may be present in up to 20% of the U.S. population. 1 Expression of ferritin, the primary tissue iron-storage protein in the liver, where most extra body iron is stored, is induced in primary or secondary iron overload disorders, resulting in increased hepatic and circulating ferritin levels. 2 However, ferritin is also an acute-phase protein and can also be induced in the setting of systemic inflammation. Hyperferritinemia has been previously observed in obesity-related chronic inflammatory conditions, such as diabetes and metabolic syndrome. We and others have previously reported that serum ferritin (SF) may be increased in the general population in relationship to alcohol consumption, as well as in chronic liver disease due to hepatitis C and alcohol. 9- 16 In such conditions, SF elevation may or may not be