OBJECTIVES: The incidence of skin and soft tissue infections (SSTI) has augmented recently in Mexico, mainly due to increases in vancomycin-resistant pathogens and immunocompromised patients. New antibiotics, such as daptomycin, have proved to be efficacious in the management of SSTI. An economic evaluation was performed to determine the most cost-effective alternative between daptomycin and linezolid for the treatment of SSTI with failure to vancomycin therapy. METHODS: A cost-effectiveness analysis was performed from an institutional perspective (Mexican Institute of Social Security, IMSS). Both drugs are included within the treatment guidelines as secondary therapy for SSTI following vancomycin failure. As required per guidelines, use of concomitant therapy with ciprofloxacin and metronidazole was also considered. Effectiveness and safety data was taken from published literature; effectiveness parameters included clinical and microbiological cure, and safety parameters included drug-related adverse events. Resource use data was obtained from the institution; total direct costs of hospitalization and treatment were considered. The source of the unit costs was the institution, current for 2010. All costs are expressed in local currency (Mexican Pesos, MXP). The time horizon was less than 1 year; no discount rate was used. A decision tree was built, considering two possible outcomes: success and failure to treatment. A probabilistic sensitivity analysis was performed through a Monte Carlo simulation with 100,000 iterations to confirm the robustness of the model. RESULTS: The results show a cost/effectiveness ratio of $52,135.67 MXP for daptomycin compared to $67,623.14 MXP for linezolid, making daptomycin a more cost-effective alternative (dominant) for the treatment of SSTI. The sensitivity analysis confirmed the robustness of the model. CONCLUSIONS: From an institutional perspective in Mexico, daptomycin is a more cost-effective (dominant) alternative than linezolid for the treatment of SSTI in patients that failed treatment with vancomycin.