There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of “stemness”‐related markers. A large‐scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial‐mesenchymal transition (EMT)‐related protein expression status of this subtype of HCCs. The expression status of stemness‐related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c‐kit) and EMT‐related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E‐cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c‐kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness‐related marker (92.0%). K19‐positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19‐negative HCCs (P < 0.05). K19 was most significantly associated with EMT‐related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease‐free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19‐positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor‐capsule formation, compared to K19‐negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease‐free survival (P = 0.032). Conclusion: K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness‐related proteins. K19‐positive HCCs showed significantly increased EMT‐related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19‐negative HCCs through the up‐regulation of EMT‐associated genes. (HEPATOLOGY 2011;)