Keywords:mesenchymal movement;amoeboid movement;metastasis;WAVE2;MLC2AbstractTumor cells can move as individual cells in two interconvertible modes: mesenchymal mode and amoeboid mode. Cytoskeleton rearrangement plays important roles in the interconversion. Previously, we reported that HAb18G/CD147 and annexin II are interacting proteins involved in cytoskeleton rearrangement, yet the role of their interaction is unclear. In this study, we found that the depletion of HAb18G/CD147 produced a rounded morphology, which is associated with amoeboid movement, while the depletion of annexin II resulted in an elongated morphology, which is associated with mesenchymal movement. The extracellular portion of HAb18G/CD147 can interact with a phosphorylation‐inactive mutant of annexin II and inhibit its phosphorylation. HAb18G/CD147 inhibits Rho signaling pathways and amoeboid movement by inhibiting annexin II phosphorylation, promotes membrane localization of WAVE2 and Rac1 activation via the integrin‐FAK‐PI3K/PIP3 signaling pathway, and promotes the formation of lamellipodia and mesenchymal movement. These results suggest that the interaction of HAb18G/CD147 with annexin II is involved in the interconversion between mesenchymal and amoeboid movement of HCC cells.