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Copper has a role in antioxidant defense, lipid peroxidation, and mitochondrial function, and copper deficiency has been linked to atherogenic dyslipidemia. We aimed to investigate the potential role of copper availability in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).Patients with NAFLD (n=124) were compared to patients with chronic hepatitis C (n=50), hemochromatosis (n=35), alcoholic liver disease (n=13), autoimmune hepatitis (n=11), and control subjects (n=27). We determined liver and serum copper concentrations with correlation to clinical, histological, and biochemical parameters in humans. The effect of dietary copper restriction on liver histology and intermediary metabolism in rats was investigated.Hepatic copper concentrations in patients with NAFLD were lower than in control subjects (17.9±8.4 vs. 31.4±8.2 μg/g;P<0.001) and in patients with other liver diseases (P<0.05 for all liver diseases). In patients with NAFLD, lower liver copper was correlated with more pronounced hepatic steatosis (R=−0.248;P=0.010), fasting glucose (R=−0.245;P=0.008), and components of the metabolic syndrome (MetS;R=0.363;P<0.001). Patients with nonalcoholic steatohepatitis (NASH;n=31) had lower hepatic copper concentrations than those with simple steatosis (n=93;P=0.038). Restriction of dietary copper in rats induced hepatic steatosis and insulin resistance (IR).Reduced hepatic copper concentrations are found in human NAFLD and are associated with more pronounced hepatic steatosis, NASH, and components of the MetS. The development of hepatic steatosis and IR in response to dietary copper restriction in rats suggests that copper availability may be involved in the development of NAFLD.