Cytokinesis failure is the primary cause of hepatocytepolyploidization. However, there are few studies onceramide synthase and polyploidy. Ceramide synthases(CerS) have six isoforms (CerS1-CerS6), each of whichcan synthesize ceramides with different acyl chain lengths(C14:0-C30:0) and possess tissue-specific distribution. Ceramide synthase 2 (CerS2) preferentially synthesizesceramides with longer acyl chains of C22 and C24. In human hepatocellular carcinoma (HCC), CerS2 geneexpression was lower compared with the normal liver. We found that the deletion of CerS2 led to abnormal hep-atic chromosome polyploidy and substantial steatosis andhepatic carcinoma in 15-month-old mice. Further stud-ies demonstrated that CerS2 plays a critical role in main-taining hepatic chromosome polyploidization via Mad2expression during cell division.