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Simple Summary Chronic inflammation is known to drive cancer initiation and progression in the liver and other organs. In different genetic mouse models, the role of the pro-inflammatory kinase Tak1 in liver cancer development has been controversial so far. To clarify the role of Tak1 in human hepatocellular carcinoma (HCC), we investigated the expression of Tak1 in a large and clinicopathologically well-characterized patient cohort with HCC. In human livers and HCCs, Tak1 is predominantly present in its isoform Tak1A localizing to the cell nucleus. Tak1 is upregulated in HCCs of the diethylnitrosamine mouse model as well as in human HCCs, independent of etiology, and is further induced in distant metastases. Overexpression of the isoform Tak1A in the HCC cell line Huh7 resulted in increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. In human HCCs, high nuclear Tak1 expression is associated with vascular invasion and short overall survival. Abstract Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.