In light of the potential antitumor function of PRG4, and the relevant involvement of its recently identified receptor, CD44, in HCC progression, we aimed to investigate the role of this PG in a patients setting, as well as test its capacity to limit the aggressive phenotype of HCC cells and enhance the in vitro cell growth-inhibitory potential of sorafenib and regorafenib. This evidence concerns the gene PRG4 and hepatocellular carcinoma.