Polyethylene glycol (PEG) is the most commonly used hydrophilic polymer in cosmetics and polymer-based drug delivery systems. PEGylation of nanocarriers has gained a lot of interest nowadays as it improves the circulation half-life and formulation stability. Recently, mRNA-based COVID-19 vaccines depend on the delivery of mRNA to the cytosol and then being transcribed into the antigenic proteins that prime the immune system to produce specific antibodies (Abs) that can protect against the coronavirus infectious diseases. PEG is considered one of the main components used in the formulation of lipid nanoparticles (LNPs) encapsulating mRNA genomic material. Despite the previous reports that PEG is considered a stealth and non-immunogenic polymer, anti-PEG Abs were detected following the treatment with PEGylated products. Unfortunately, anti-PEG Abs were found not only in patients treated with PEGylated therapeutics, but also in healthy individuals who had never used a PEGylated product before. Several cases of hypersensitivity have been reported following mRNA-based COVID-19 vaccination. It is thought that PEG plays a crucial role in the development of anaphylactic reactions reported post-vaccination. So, in our study, we tried to highlight the mRNA-based COVID-19 vaccine products and the role of PEG in the formulation of mRNA-LNPs. Also, we focused on the immunogenicity of PEG and its effect on the clearance of PEGylated therapeutics. In addition, we tried to demonstrate the potential role of PEG in these reactions. Finally, we introduced the possible hypothesis to overcome PEG-induced hypersensitivity and the recent recommendations should be taken into consideration before PEGylated products are administrated.