PEGylation is currently the technique of choice to extend the in-vivo circulation half-life of therapeutic proteins. Nevertheless, the PEGylation reaction is not yet fully described, particularly concerning the development of a proper kinetic model. In this work, we propose a detailed model which describes the rate of protein amine PEGylation with functionalized PEG esters by accounting for the specific reactivity of the various residues and for the shielding effect generated by the already conjugated PEG chains. The proposed kinetic rate constants are derived so as to explicitly include diffusion limitations, heterogeneous reactivities and the steric hindrance caused by the polymer layer surrounding the PEGylated proteins. With illustrative purposes, this new model has been applied to the simulation of lysozyme PEGylation at the lysine residues with PEG esters of various molecular weights and with various PEG to protein molar ratios. (C) 2015 Elsevier Ltd. All rights reserved.