The aim of this retrospective study was to determine the potential reversibility of hepatitis C virus (HCV) cirrhosis with the combined antifibrotic effects of interferon-alpha and the increasing frequency of sustained virologic response. Sixty-four HCV-cirrhotic immunocompetent patients who underwent antiviral therapies (interferon-alpha with or without ribavirin) and pretreatment and posttreatment liver biopsies were included (group 1). Resolution of cirrhosis was defined as a decrease in the fibrosis score from 4 to 2 or less by the Metavir score after blinded analysis by 2 independent pathologists. An additional group of 4 HCV-infected dialysis patients (group 2) who had received antiviral treatment, among whom 3 underwent a combined renal and liver transplantation allowing the analysis of the whole liver, was also studied. In 5 (all stage Child A) of the 64 cirrhotic patients (7.8%), the final biopsy showed only F2 to portal and periportal fibrosis with rare fibrous septa without nodule formation. Four of these 5 were complete sustained responders (negative PCR and normal ALT), and 1 was a relapser. In group 2, reversibility of cirrhosis was observed in 3 of the 4 patients and was clearly shown in 2 patients by the analysis of the whole-liver examination at the time of the hepatectomy preceding the transplantation. In conclusion, long-lasting suppression of the necroinflammatory activity of liver disease and/or antifibrogenetic effects of interferon-alpha may allow regression of cirrhosis.