It is generally believed that liposomes modified with polyethylene glycol (PEG) have no or lower immunogenicity.  However, based on many recent literatures, when the PEGylated liposomes were repeatedly applied to the same animal, the immune responses occurred.  The first injection of PEGylated liposomes resulted in a reduction in the circulation time and an increase in hepatic and splenic accumulation of the second dose of PEGylated liposomes in a time-interval, which was called “accelerated blood clearance (ABC)” phenomenon.  Such immunogenicity of PEGylated liposomes presents a barrier in the research of liposomal formulations and their use in the clinics.  This review focused on the definition, the method of verification, the development of  the reason for ABC phenomenon, influencing factors of ABC phenomenon, and discussed if other PEGylated nanocarriers also induce ABC phenomenon.