Poly(ethylene glycol) (PEG) is widely used in nanomedicine design, but emerging PEG immunogenicity in the general population is of therapeutic concern. As alternative, polyoxazolines are gaining popularity, since “polyoxazolinated” nanoparticles show long-circulating properties comparable to PEGylated nanoparticles in mice. Here, we show species differences in opsonization and differential uptake by monocytes and macrophages of nanoparticles coated with either poly-2-methyl-2-oxazoline or poly-2-ethyl-2-oxazoline. These nanoparticles evade murine opsonization process and phagocytic uptake but porcine ficolin 2 (FCN2), through its S2 binding site, recognizes polyoxazolines, and mediates nanoparticle uptake exclusively by porcine monocytes. In human sera, FCN opsonization is isoform-dependent showing inter-individual variability but both FCN2 and complement opsonization promote nanoparticle uptake by human monocytes. However, nanoparticle uptake by human and porcine macrophages is complement-dependent. These findings advance mechanistic understanding of species differences in innate immune recognition of nanomaterials’ molecular patterns, and applicable to the selection and chemical design of polymers for engineering of the next generation of stealth nanoparticles.