Background & Aims: Treatment of chronic hepatitis C (CHC) results in an average sustained viral response (SVR) rate of 54%-63%. Most previous studies have not separately reported SVR rates for patients who have CHC and concomitant significant hepatic steatosis (>33%) or histologic evidence of steatohepatitis (SH). The aim of this study was to evaluate SVR in patients with CHC plus steatosis or SH on biopsy examination, compared with a group of controls with CHC and no significant steatosis or SH. Methods: Our surgical pathology database and clinical files were queried for CHC between 1997 to 2002. Biopsy specimens with both CHC and significant steatosis (>33%) or SH were categorized as group 1. Of the patients treated with antiviral therapy, information on either SVR (hepatitis C virus [HCV] RNA negative at 6 months posttreatment) or lack of SVR (nonresponse as early as 12 weeks into therapy and relapsers) with either interferon (IFN)/ribavirin or pegylated IFN/ribavirin was found in 84 patients. A control group (group 2) of 231 CHC patients was identified by using a 2-year database (January 2000-June 2001) of patients without evidence of greater than 33% steatosis or SH. Results: The overall SVR was 28% in group 1, compared with 44% for group 2 (P =. 001). For HCV genotype 1, the SVR was 23% vs 34% for group 2 (P =. 19). For HCV genotypes 2 and 3, the SVR was 42% vs 78% for groups 1 and 2 (P =. 008), respectively. Conclusions:Overall SVR for patients with HCV and significant steatosis or SH is considerably lower than for HCV and steatosis less than 33% and no SH.