PurposePeriprosthetic joint infections induced by methicillin-resistantStaphylococcus aureus(MRSA) pose a major socioeconomic burden. Given the fact that MRSA carriers are at high risk for developing periprosthetic infections regardless of the administration of eradication treatment pre-operatively, the need for developing new prevention modalities is high.MethodsThe antibacterial and antibiofilm properties of vancomycin, Al2O3nanowires, and TiO2nanoparticles were evaluated in vitro using MIC and MBIC assays. MRSA biofilms were grown on titanium disks simulating orthopedic implants, and the infection prevention potential of vancomycin-, Al2O3nanowire-, and TiO2nanoparticle-supplemented Resomer® coating was evaluated against biofilm controls using the XTT reduction proliferation assay.ResultsAmong the tested modalities, high- and low-dose vancomycin-loaded Resomer® coating yielded the most satisfactory metalwork protection against MRSA (median absorbance was 0.1705; [IQR = 0.1745] vs control absorbance 0.42 [IQR = 0.07];p= 0.016; biofilm reduction was 100%; and 0.209 [IQR = 0.1295] vs control 0.42 [IQR = 0.07];p< 0.001; biofilm reduction was 84%, respectively). On the other hand, polymer coating alone did not provide clinically meaningful biofilm growth prevention (median absorbance was 0.2585 [IQR = 0.1235] vs control 0.395 [IQR = 0.218];p< 0.001; biofilm reduction was 62%).ConclusionsWe advocate that apart from the well-established preventative measures for MRSA carriers, loading implants with bioresorbable Resomer® vancomycin-supplemented coating may decrease the incidence of early post-op surgical site infections with titanium implants. Of note, the payoff between localized toxicity and antibiofilm efficacy should be considered when loading polymers with highly concentrated antimicrobial agents.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00264-023-05757-2.