Systemic antibiotics and in situ antimicrobial-impregnated cement are frequently used concomitantly in the management of prosthetic joint infections. The combination of in situ and systemic daptomycin in such settings is not well documented. Current evidence from in vitro studies suggests in situ daptomycin-impregnated cement may be an alternative to vancomycin for the management of prosthetic joint infections. We report a case of a 77-year-old man who received both in situ and systemic daptomycin for a methicillin-resistant Staphylococcus aureus prosthetic joint infection complicated by linezolid resistance and severe vancomycin allergy. The combination of daptomycin plus oxacillin was also used, and its potential role to counter evolving daptomycin resistance is discussed.