Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n 5 229]; Hannover, Germany [n 5 171]; Lyon, France [n 5 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P 5 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P 5 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P 5 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P 5 0.875) and did not influence clinical or biological variables. Conclusion: The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage. (HEPATOLOGY 2011;54:60-69) H epatitis C virus (HCV) is a major health burden with 130 to 170 million people infected, representing nearly 3% of the worldwide population. 1 HCV infection progresses to chronicity in 80% of cases, 2 and chronic hepatitis C (CHC) is one of the leading causes of cirrhosis, hepatocellular carcinoma, and liver transplantation in Western countries. 3 CHC patients are at high risk of liver fibrosis,