BACKGROUND/AIMS: In vitro and animal data suggest that alcohol and hepatitis C virus (HCV) proteins might interfere with Stat3 signaling, a potential regulator of liver cell apoptosis and proliferation. METHODS: We assessed Stat3 expression, activity and the apoptotic-proliferation balance in end-stage HCV and alcoholic liver disease (ALD) in man. Explanted livers of HCV and ALD patients were compared to normal and primary biliary cirrhosis (PBC) livers. RESULTS: Although Stat3 expression and phosphorylation was not altered in HCV and ALD cirrhosis, Stat3 DNA-binding was not detected in all ALD and most HCV samples. Deficient Stat3 DNA-binding was associated with high Pias3 expression, but not with increased Socs3 levels. Bcl-2 was up-regulated in HCV and ALD together with decreased Caspase3 activity. Compared to base-line cell proliferation in normal donor livers, HCV cirrhosis showed a marked reduction in cyclin D1 and PCNA, whereas both markers were only slightly reduced in ALD. CONCLUSIONS: End-stage HCV and ALD cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. Therefore, impaired activation of Stat3 target genes might contribute to disturbed liver regeneration and repair. The attempt in cirrhotic livers to favor anti-apoptotic over pro-apoptotic pathways is not sufficient to compensate for the low cellular proliferation rates.