The surgical repair of pelvic organ prolapse using synthetic mesh can fail because of slow or partial implant integration due to poor biocompatibility or infection. As systemic antibiotic prophylaxis has only limited success, we have developed a system that coats standard polypropylene mesh with clinically relevant antibiotics. Amoxicillin and ofloxacin are both released from the mesh in vitro at high levels over 3 days, preventing adhesion and biofilm formation by a clinical isolate of E. coli. In an in vivo incisional hernia repair model in rats, the antibiotic-coated mesh results in appropriate tissue integration with adequate vascularization and collagen formation. When implanted animals are infected with virulent E. coli, both antibiotic coatings provide full protection against infection (as assessed both clinically and microbiologically), thus demonstrating their bioavailability. This method is a specific approach for producing a therapeutic coating that could reduce postsurgical infections. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 100B: 471–479, 2012.