BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly common cause of bacteremia and endocarditis. The cost-effectiveness (CE) of daptomycin was compared with that of vancomycin-gentamicin in patients with MRSA bacteremia with or without endocarditis. METHODS With use of data from an open-label, randomized study comparing daptomycin with vancomycin-gentamicin in the aforementioned patient population, 3 cost strata were considered: (1) study drug acquisition (daptomycin, $0.37/mg; vancomycin, $7/g; and gentamicin, $0.12/mg); (2) stratum 1 plus the cost of therapy for treatment failures and adverse events, therapeutic drug monitoring, and preparation and administration of all medications; and (3) stratum 2 plus hospital bed costs. Drug costs were based on mean wholesale price, with other costs based on those for a typical community hospital. Cost-effectiveness ratios were calculated as cost divided by proportion of successes. Sensitivity analyses were performed by varying the study drug cost. RESULTS Forty-five (20 successes) and 44 (14 successes) patients received daptomycin and vancomycin-gentamicin, respectively. The respective median cost-effectiveness ratios for daptomycin and vancomycin-gentamicin for each cost stratum were as follows: $4082 (range, $1062-$13,893) and $560 (range, $66-$1649) for stratum 1 (P < .001); $4582 (range, $1109-$21,882) and $1635 (range, $163-$33,444) for stratum 2 (P = .026); $23,639 (range, $6225-$141,132) and $26,073 (range, $5349-$187,287) for stratum 3 (P = .82). Sensitivity analyses indicated that if the cost of vancomycin was $0, strata 3 cost-effectiveness ratios did not differ ($23,639 and $25,668, respectively; P = .85). Similar results between groups were seen among patients with bacteremia. CONCLUSIONS When all costs of therapy were considered, the cost-effectiveness of daptomycin and vancomycin-gentamicin was similar, even if the cost of vancomycin was $0.