In light of research reporting abnormal pharmacokinetic behavior for therapeutics and formulations containing poly(ethylene glycol) (PEG), a renewed emphasis has been placed on exploring alternative surrogate materials and tailoring specific materials to distinct nanomedicine applications. Poly(2-oxazolines) (POx) have shown great promise in this regard; however, a comparison of POx and PEG interactions with components of the immune system is needed to inform on their distinct suitability. Herein, the interaction of isolated immune cells following injection of hyperbranched polymers comprised of PEG or hydrophilic POx macromonomers was determined via flow cytometry. All materials showed similar association with all of the splenic immune cells analyzed. Interestingly, splenic CD68hi and CD11bhi macrophages showed similar levels of polymer association, despite CD11bhi being a smaller population, suggesting CD68 is linked to increased recognition and phagocytosis of these nanomaterials. This is of interest given that CD68 is a scavenger receptor and directly facilitates the clearance of cellular debris and promotion of phagocytosis, as opposed to CD11b, which is associated with the mediating inflammation via the production of cytokines as well as complement-mediated uptake of foreign particles. In the liver, PEG and poly(2-methyl oxazoline) hyperbranched polymers showed no discernible differences in their cellular association, while hyperbranched poly(2-ethyl oxazoline) showed increased association with dendrocytes and CD68hi macrophages, suggesting that this material exhibited a greater propensity to interact with components of the immune system. This work highlights the importance of how subtle changes in chemical structure can influence the immune response.