Histological response is defined as an improvement in the severity of liver inflammation with or without an improvement in fibrosis in patients following treatment for an acute or chronic liver disorder. Histological response occurs in patients with chronic hepatitis C virus (HCV) infection who have had a sustained virological response following treatment with interferon (IFN) therapy and in a percentage of nonresponders. Continuing IFN long term as maintenance therapy has been shown to prevent histological progression in patients who had both a marked decline in serum HCV RNA level during treatment and a histological response on repeat histological analysis. Prospective controlled trials are currently evaluating the benefits of low-dose maintenance therapy with pegylated IFN in HCV patients who have failed to achieve sustained virological response. In the future, the development of serum markers of fibrosis may allow for monitoring of hepatic fibrosis and histological response to therapy without the need to perform repeat liver biopsy.