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Staphylococcus aureus is a major cause of bacteremia and endocarditis in adults. Vancomycin is the standard therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Although clinical failure associated with the development of reduced susceptibility to vancomycin during the course of treatment for MRSA bacteremia has been reported infrequently, such an occurrence is very serious. We report a case of 43-year-old woman with of MRSA bacteremia, who relapsed after initial, apparently successful vancomycin treatment and developed left-sided endocarditis and vertebral osteomyelitis. Two weeks into her second admission, the vancomycin minimal inhibitory concentration rose from ≤ 2 μg/mL (susceptible) to 4 μg/mL (intermediate). The antibiotic was changed to daptomycin. Subsequent blood cultures were negative and sepsis resolved.