The coordinate expression of cytokeratin (CK) 7/20 has been useful to distinguish among carcinomas arising from different primary sites. The importance of CK typing in liver pathology has been recognized as a phenotypic marker as well. We investigated CK7/20 profiles in 25 hepatocellular carcinomas (HCCs), 27 biliary tract carcinomas (BCs), and 25 metastatic gastrointestinal adenocarcinomas (MCs). In BCs and MCs, we analyzed the relationships among tumor size, the percentage of CK20-reactive tumor cells (CK20%), and the percentage of tall columnar tumor cells (TC%). In the majority, HCCs were CK7-/20- (76%); BCs, either CK7+/20+ (41%) or CK7+/20-(56%), and MCs were CK7-/20+ (82%). In HCCs, aberrant CK7+ (20%) were associated with CK19-coexpressing pseudoglandular pattern suggesting ductular metaplasia, whereas aberrant CK20+ (4%) was associated with cellular pleomorphism accompanied by occasional cytoplasmic filamentous structures and by increased Ki-67 and p53 expression. Variable expressions according to primary sites were noted in BCs and MCs: cholangiocarcinomas (CCs) (12/19) and gallbladder carcinomas (2/3) were frequently CK20-, whereas extrahepatic bile duct carcinomas (4/5) were frequently CK20+; most MCs from colorectum (MCCs) (21/23) were CK7-, whereas all MCs from stomach (2/2) were CK7+. In particular, profiles for CCs and MCCs were differential in most cases: CK7+/20- (63%) versus CK7-/20+ (87%). In BCs, CK20% was also correlated with TC% (p = 0.002). In the majority, carcinomas involving the liver showed differential CK7/20 profiles according to their origin, suggesting their diagnostic utility. The aberrant or variable CK expressions seemed to be associated with the adoption of certain phenotypes as well.