Background: Keratin (K) 8 ad 18 are important intermediate filaments in liver.Steatohepatitis (SH), a progressive metabolic liver disease occurrs in about 20 % of alcoholics and up to 50 % of obese type Ⅱ diabetics.SH is a major precondition for the development of hepatocellular cancer (HCC).SH is typified by characteristic morphological features comprising steatosis, hepatocyte ballooning frequently associated with the occurrence of cytoplasmic protein aggregates termed Mallory-Denk bodies (MDBs) consisting predominantly of misfolded K 8 and 18 proteins.In this study we aimed at elucidating the impact of the loss of K 18 on liver cancer development in mice.Material and Methods: K18-/-(129 Ola background) mice were bred and hosted until the age of 17 months.Then they were investigated for the occurrence of liver tumors.Results: We discovered that aged K18-/-mice spontaneously develop the morphological spectrum of SH while aged wild-type mice developed simple steatosis.Moreover aminotransaminase levels were elevated in these mice.Interestingly,91% of male and 46% of female 17 month-old K18-/-mice developed liver tumors revealing typical morphological and genetic features of HCC.75% of male and 36% of female age-matched K18+/-mice developed HCC.Conclusions:K18-/-mice represent a novel spontaneous SH and HCC model.Changes in hepatocellular K18 integrity seem to determine the susceptibility towards SH and oncogenic events finally leading to HCC.These data propose that alterations in the keratin cytoskeleton are critical for hepatocarcinogenesis.