PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug, while it also causes some disadvantages of which cannot be neglected. The available data manifests that polyethylene glycol (PEG) itself shows potential risk, such as immunogenicity of the PEG and PEG-containing vacuoles in cells observed with PEGylated biologicals. Decreased activity and heterogeneity are also the negative aspects of PEGylation. The unfavorable impacts which are brought by the PEGylation are described here with examples of modified therapeutic proteins on the market and used in the clinical trials.