On the basis of cross-sectional studies, it has been proposed that hepatic steatosis is a cytopathic effect of hepatitis C virus (HCV) genotype 3 but not genotype 1 infections. We tested this hypothesis by examining whether antiviral treatment altered hepatic steatosis in chronic hepatitis C. In 28 patients with genotype 1 and 34 with genotype 3 HCV, we determined the severity of steatosis in pre- and posttreatment liver biopsies using computer-assisted morphometric image analysis as well as conventional semiquantitative scoring. Before treatment, hepatic steatosis was present in 16 (57%) patients infected with HCV genotype 1 and 21 (62%) of those with genotype 3. Sustained viral response (SVR) was achieved in 9 (32%) patients with genotype 1 and 22 (65%) with genotype 3. In neither group were there significant changes in body weight or alcohol consumption between pre- and posttreatment biopsies. In patients with HCV genotype 1, there was no change in hepatic steatosis after treatment, irrespective of the treatment response. Among those infected with genotype 3, SVR significantly reduced steatosis (P <.001), but there was no change in steatosis among those without a SVR. By logistic regression analysis, SVR was the only variable predictive of improvement in hepatic steatosis (OR = 36, 95% CI = 2.7-481, P =.007). In conclusion, these data provide strong support for a direct causal association between HCV genotype 3 infection and hepatic steatosis.