Generally, it has been thought that PEG-conjugated nanocarriers are non-immunogenic. However, many reports have revealed that unexpected immune responses occur with such PEG-conjugated nanocarriers. The Most important one is the rapid clearance of PEGylated nanocarriers upon repeated administration which is called accelerated blood clearance phenomenon involving the production of antibodies against nanocarrier components, which reduces the safety and effectiveness of the encapsulated therapeutic agent. Such immunogenicity of PEGylated nanocarriers is a potential concern in the evaluation and clinic use of PEGylated therapeutics. Accordingly, screening of the immunogenicity of nanocarriers-based therapeutics is a prerequisite before their adoption into clinical settings to disclose any possible interactions with immune system. This review gives an overview of PEGylated liposomes, immunogenicity of PEG, explanation of accelerated blood clearance (ABC) phenomenon, its mechanism, various factors affecting it and side effects of PEGylated liposomes.