Proteins are promising therapeutics with several design challenges, such as their inherent immunogenicity due to their exogenous source or short circulation time. The common solution to such issues is the chemical conjugation of the amphiphilic polymer poly(ethylene glycol) (PEG), a process known as PEGylation. However, several studies demonstrated a decrease in protein bioactivity or an increase in the presence of specific antibodies post PEGylation, highlighting the importance of an alternative strategy. Here we compare the performance of a superhydrophilic zwitterionic polymer in protecting an immunogenic protein to PEG in (i) the maintenance of enzyme activity and stability post modification, (ii) mitigation of the antibody response elicited by the polymer and any subsequent effect on pharmacokinetics, and (iii) minimization of host response toward the underlying protein. In contrast to PEG, zwitterionic conjugation decreases host antibody response without sacrificing bioactivity or generating polymer-specific antibodies. (C) 2016 Elsevier Ltd. All rights reserved.