Poly(ethylene glycol) (PEG) is widely used in engineering of clinical nanomedicines; however, the emerging PEG immunogenicity is compromising their therapeutic efficacy. Polyoxazolines are gaining popularity as PEG alternatives, since “polyoxazolination” confers stealthing behaviour to nanomedicines in the preclinical mouse model. Here, using nanoparticles coated with either poly-2-methyl-2-oxazoline (PMOXA) or poly-2-ethyl-2-oxazoline (PEOXA), we show species differences in nanoparticle opsonization and phagocytic cell responses. PMOXA- and PEOXA-coated nanoparticles evade murine serum opsonization and phagocytic clearance. Polyoxazolinated nanoparticles, however, undergo differential opsonization in porcine and human sera, resulting in nanoparticle recognition by different phagocytic cells differently. We identify ficolin 2 (FCN2) as a monocyte-specific opsonin in pigs, whereas in human sera, FCN opsonization is isoform-dependent with inter-individual variability. Polymer recognition is through the S2 domain of FCN2 which sense hydrogen bond forming chemical moieties and hydrophobic patterns of polyoxazolines. Contrary to the porcine model, both FCN2 and complement promote nanoparticle uptake by human monocytes. On the other hand, nanoparticle uptake by human and porcine macrophage is complement-dependent. These findings highlight the importance of species differences in innate immune recognition of nanomaterials’ molecular patterns, and are relevant to the selection and chemical design of polymers for engineering of the next generation of stealth nanoparticles.