BACKGROUND: Evidence supporting beta-lactam plus vancomycin synergy for methicillin-resistant (MRSA) continues to grow. Current evidence demonstrates that combination therapy is associated with shorter time to blood sterilization than vancomycin monotherapy. However, this combination has not been reported as salvage therapy for persistent MRSA bacteremia. CASE REPORT: We report a case of an 81-year-old male who was successfully treated with vancomycin plus nafcillin after failing vancomycin monotherapy, daptomycin monotherapy, and daptomycin plus gentamicin combination therapy. The patient originally presented with sepsis from a suspected urinary tract infection. Blood cultures drawn on days 1, 3, 5, 15, 19, 23, and 28 remained positive for MRSA despite multiple antimicrobial therapy changes. On day 29, therapy was changed to vancomycin plus nafcillin. Blood cultures drawn on day 32 remained negative. After 11 days, nafcillin was changed to piperacillin-tazobactam due to an infected decubitus ulcer. The combination was continued for 42 days after achieving blood sterility, 71 days after the patient originally presented. Evidence regarding salvage therapy for persistent bacteremia is sparse and is limited to case reports and case series. CONCLUSION: This case report supports that vancomycin plus an anti-staphylococcal beta-lactam combination should be further studied as salvage therapy for persistent MRSA bacteremia.