Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. (HEPATOLOGY 2004;40:459–466.)