OBJECTIVES: To determine the most cost-effective intravenous antibiotic treatment for complicated skin and skin-structure infections (cSSI) in public health care institutions in Mexico. METHODS: A cost-effectiveness study with institutional perspective was conducted comparing the use of either i.v. Daptomycin (DAP), i.v. Vancomycin (VAN) or i.v. Linezolid (LIN) as first-line and/or second-line antibiotic therapy. Data was collected from a systematic review which included the most recent published articles measuring clinical improvement, length of stay at hospital services and adverse events due to the use of any of three alternatives. A decision tree with Bayesian approach was designed to simulate the use of resources based on patient’s prognosis considering clinical success as the best health state, reached in either short hospital stay or long hospital stay, and a therapeutic failure of first-line antibiotic therapy (DAP, VAN or LIN) which caused the use of a second-line antibiotic therapy (DAP or LIN depending on first election). Costs calculation considered hospital stay, concomitant medication and selected antibiotic treatment. Results were evaluated with incremental analysis and one-way sensitivity analysis of the most uncertain variables. RESULTS: The use of DAP as first-line therapy results in the lowest cost per clinical success (CS) (DAP: US$3,405.00/CS; VAN:US$3,550.00/CS; LIN:US$3,870.00/CS). In case of therapeutic failure of DAP, the use of LIN as second-line therapy resulted in the lowest total cost per clinical success (DAP-LIN: US$3,255.00/CS; VAN-DAP: US$3,310.00/CS; VAN-LIN: US$3,310.00/CS; LIN-DAP: US$3,423.00), reaching 98% of CS. The sensitivity analysis varying clinical success rates of every evaluated alternative confirmed the robustness of base study. CONCLUSIONS: Daptomycin is the most cost-effective alternative in the treatment of cSSI 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.