Elevated phospholipase D (PLD) expression prevents cell cycle arrest and apoptosis. However, the roles of PLD isoforms in cell proliferation and apoptosis are incompletely understood. Here, we investigated the physiological significance of the interaction between PLD2 and protein kinase CKII (CKII) in HCT116 human colorectal carcinoma cells. PLD2 interacted with the CKII${eta}$ subunit in HCT116 cells. The C-terminal domain (residues 578-933) of PLD2 and the N-terminal domain of CKII${eta}$ were necessary for interaction between the two proteins. PLD2 relocalized CKII${eta}$ to the plasma membrane area. Overexpression of PLD2 reduced CKII${eta}$ protein level, whereas knockdown of PLD2 led to an increase in CKII${eta}$ expression. PLD2-induced CKII${eta}$ reduction was mediated by ubiquitin-dependent degradation. The C-terminal domain of PLD2 was sufficient for CKII${eta}$ degradation as the catalytic activity of PLD2 was not required. Taken together, the results indicate that the C-terminal domain of PLD2 can regulate CKII by accelerating CKII${eta}$ degradation in HCT116 cells.