Surface coatings with so-called protei n-repellent or nonfouling polymers have become indispensable for the development of modern therapeutic and diagnostic medical devices such as biosensors, drug-delivery capsules, and biomedical implants. Nowadays, poly(ethylene glycol) (PEG) is routinely used for these purposes. However, there is increasing evidence that PEG has limited long-term stability, particularly in vivo. Here we investigate poly(2-methyl-2-oxazoline) (PMOXA) as a potential alternative polymer. We designed comb copolymers consisting of a polycationic poly(L-lysine) backbone and PMOXA side chains by analogy to precisely studied and highly protein-repellent PEG-based systems. Using optical waveguide lightmode spectroscopy, we quantitatively compare the in situ self-assembly of the comb copolymers on negatively charged surfaces and the exposure of the formed monolayers to full human serum. We find that the PMOXA-based coatings with an optimal side-chain grafting density eliminate protein adsorption to a level of <2 ng/cm(2); that is, they quantitatively equal the protein-repellent properties of the best PEG-based coatings.