Metabolic liver diseases include disorders ranging from hepatic steatosis to steatohepatitis and cirrhosis. Finally, hepatocellular carcinoma can occur as an end stage of these disorders. With obesity, the metabolic syndrome and alcohol consumption, hepatic viral infections are one of the major causes of metabolic liver disorders. Among them, hepatitis C virus (HCV) is of particular importance. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been reported to be downregulated in the liver of obese rats and patients having hepatic steatosis. Additionally, liver-specific PTEN knockout mice develop steatosis in the liver then evolving into steatohepatitis and hepatocellular carcinoma. In this work, we showed that PTEN protein expression is downregulated by HCV infection in patients having genotype-induced steatosis and that this downregulation can trigger lipid droplet accumulation and insulin resistance. We also established that PTEN downregulation by HCV is able to improve viral release from infected cells.