OBJECTIVES To determine whether the use of i.v. Daptomycin or i.v. Vancomycin is the most cost-effective alternative for the treatment of infective endocarditis in public health care institutions in Mexico METHODS A cost-effectiveness study was performed considering an institutional perspective and comparing the use of the evaluated alternatives as first-line antibiotic therapy. A systematic review was performed in order to collect data about clinical success, length of stay at hospital services and adverse events due to the use of either i.v. Daptomycin or i.v. Vancomycin. The use of resources matrix considered the selected antibiotic therapy, concomitant medication, length of stay at hospital services, and a second-line antibiotic therapy in case of failure. A decision tree with Bayesian approach was designed to simulate the use of resources. Patient's outcomes were supposed to be clinical success (in either short hospital stay or long hospital stay) and therapeutic failure which can be caused by death or lack of efficacy of the antibiotic. Results were evaluated with incremental analysis and one-way sensitivity analysis of the most uncertain variables were also conducted. RESULTS The use of i.v. Daptomycin results in the lowest total cost (DAP: $7,847.00 USD; VAN:$7,990.00 USD) and the lowest cost per clinical success (CS) (DAP: $17,754.00 USD/CS; VAN:$23,083.00 USD/CS) compared with i.v. Vancomycin. The sensitivity analysis varying clinical success rates of every evaluated alternative showed robustness of base study. CONCLUSIONS Daptomycin is the most cost-effective alternative in the treatment of Infective Endocarditis and MRSA Bacteremia when used as first-line antibiotic therapy, since its use reduces the length of hospital stay reducing expenses of public health system budget in Mexico. The use of Daptomycin can be considered as safer when compared to use Vancomycin, because it has been reported less frequently event adverse in long term treatments.