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Hepatic steatosis may promote progression of chronic hepatitis C (CHC). Microsomal triglyceride transfer protein (MTP) is required for assembly and secretion of ApoB lipoprotein and is implicated in hepatitis C virus (HCV)-related steatosis. The MTP −493G/T polymorphism may promote liver fat accumulation, but its role in HCV-related steatosis is still unclear.Two hundred ninety-eight CHC patients were studied and genotyped for MTP −493G/T variants. Hepatic MTP mRNA expression and activity were determined in a subgroup.Patients with grades 2/3 steatosis were older, had a higher body mass index (BMI), more advanced fibrosis and lower MTP mRNA expression and carried more often HCV genotype 3 and the MTP T allele. Age, BMI, HCV-3 and MTP T allele [odds ratio (OR) 2.05; 95% confidence interval (CI) 1.2-3.53; P=0.009] were independent risk factors for steatosis grades 2/3, and in HCV genotype non-3 patients, the MTP T allele was the strongest predictor for steatosis grade 2/3 (OR 2.17; 95% CI 1.22-3.86; P=0.008). Moreover, TT carriers had higher high-density lipoprotein (65.6±14.6 vs 56.1±16.2 mg/dl; P=0.003) and apolipoprotein AI (1.80±0.3 vs 1.60±0.3 g/L; P=0.005) levels than G allele carriers.Chronic hepatitis C patients with the MTP −493T allele reveal higher grades of steatosis, indicating a relevant contribution to liver fat accumulation, particularly in HCV non-3 patients.