SEPT2 plays an important role in cell division through its effect on cytoskeletons. It is a GTP-binding protein and can also form filament with SEPT6 and SEPT7. Knockdown of SEPT2, 6, and 7 causes stress fibers to disintegrate and then cells lose polarity and divide abnormally. Increasing evidence has shown that septins are related to the regulation of cell proliferation. In this study, the expression of SEPT2 was first identified to be up-regulated in human hepatoma carcinoma cells (HCC). In addition, SEPT2 was found to be phosphorylated on Ser218 by casein kinase 2 (CK2), which was also overexpressed in HCC. By overexpressing SEPT2 and its S218A mutant in SMMC7721 and L02 cell lines, we confirmed that the phosphorylation of SEPT2 on Ser218 by CK2 was crucial to the proliferation of HCC. These results suggest that SEPT2 might be a promising target for liver cancer therapy.