Poly(ethylene glycol) (PEG) conjugation has been the gold standard to ameliorate the pharmacokinetic (PK) and immunological profiles of proteins. PEG polymer does become immunogenic once attached to proteins, evoking PEG‐specific antibody (Ab) responses. The anti‐PEG Abs could cause PEGylated biologic treatments to fail and even result in lethal adverse reactions. Thus the zwitterionic poly(carboxybetaine) (PCB) has been introduced as a PEG substitute for protein modification. Addressed herein is anti‐polymer Ab induction by conjugating PEG and PCB polymers to a series of carrier proteins with escalating immunogenicity. Results indicate that titers of PEG‐specific Abs were quantitatively correlated to the immunogenicity of carrier proteins, whereas the generation of PCB‐specific Abs was minimal and insensitive to increased protein immunogenicity. This work provides insight into the immunological properties of PEG and PCB and has far‐reaching implications for the development of polymer‐protein conjugates. Risk management: Poly(ethylene glycol) (PEG) and zwitterionic poly(carboxybetaine) (PCB) as a promising PEG substitute were explored for their immunogenic risks. A strong quantitative correlation between the level of PEG‐specific antibodies (Abs) and the immunogenicity of proteins carrying PEG was observed, revealing the propensity of PEG to become immunogenic. In contrast, PCB manifested low immunogenic risk, as PCB‐specific Abs were negligible.