OBJECTIVES: To establish a cost-effective intravenous antibiotic therapy in the treatment of Infective Endocarditis and Bacteremia. METHODS: A cost-effectiveness study was performed considering the expenses and use of resources of Mexican Public Health Institutions. The study was based on a decision tree with Bayesian approach defining three different health states: clinical success (within short or long hospital stay frame), therapeutic failure, and death. The alternatives compared were: a) i.v. Vancomycin (VAN) as a first-line antibiotic therapy followed by a second-line antibiotic therapy in therapeutic failure, or b) i.v. Daptomycin (DAP) as a first-line or second-line antibiotic therapy. The most recent published data concerning efficacies, length of hospital stay and adverse events were included in the study. Results were evaluated with incremental analysis and one-way sensitivity analysis of most uncertain variables. RESULTS: The use of i.v. Daptomycin as first-line antibiotic therapy represents savings of US$4,619.00 per patient reaching clinical success (CS) when compared to the use of i.v. Vancomycin as first-line antibiotic therapy (DAP-VAN: US$21,168.00/CS; VAN-2nd line antibiotic: US$25,787.00/CS). A greater proportion of patients are more likely to attain clinical success when DAP is used as first-line antibiotic therapy (DAP-VAN: 62%; VAN-2nd line antibiotic: 54%) due to a less frequent development of adverse events compared to the use of VAN. The sensitivity analysis varying clinical success rates of every evaluated alternative demonstrated the robustness of the base study. CONCLUSIONS: Daptomycin is the most cost-effective alternative in the treatment of Infective Endocarditis and Bacteremia when used as first-line antibiotic therapy since it decreases hospital expenses due to a reduced hospital stay and results in a greater proportion of patients reaching clinical success. The use of Vancomycin in long term treatments is associated with a higher frequency of adverse events which can cause treatment interruption resulting in therapeutic failure.