Endocytosis is a cellular function which is likely to take part in HCC development due to its important role in regulating the abundances of vital signaling receptors. In this study, we aimed to investigate the expression of endocytosis-associated proteins in HCCs with various differentiation grades. Therefore, we analyzed 36 tissue specimens from HCC patients via label-free LC-MS/MS including 19 HCC tissue samples with different degrees of histological grades and 17 corresponding non-tumorous tissue controls. Following label-free analysis the abundances of SCAMP3 and CLTC were immunohistochemically examined in tissue sections of 84 HCC patients. We demonstrate the novel association of several endocytosis-associated proteins, in particular SCAMP3 with HCC progression.