OBJECTIVES To evaluate the cost-effectiveness of daptomycin versus vancomycin in complicated skin and soft structure infections (cSSSI). METHODS A decision analytic (DA) model was developed to evaluate the cost-effectiveness of daptomycin versus vancomycin in cSSSI. The payer perspective was adopted and total direct costs related to cSSSI were measured. Efficacy (cure) was defined as a patient who was treated empirically with the study drug, had a positive culture of Methicillin-resistant Staphylococcus aureus did not relapse at the test of cure. Previous literature was used to determine the parameters of the model. Costs were determined from 2008 Drug Red Book and Decision Support System database. Primary outcome was the incremental cost-effectiveness ratio (ICER) of daptomycin over vancomycin. One-way sensitivity analyses was performed for all parameters and presented in a tornado diagram. Probabilistic sensitivity analysis was performed on all parameters using 10,000 trial simulations. RESULTS In the base-case analysis, daptomycin and vancomycin arms had total direct costs of $11,162.88 and $16,307.74, respectively. Cure probabilities for patients in the daptomycin and vancomycin arms were 51.6% and 40.2%, respectively. Cost-effectiveness ratio for daptomycin and vancomycin were $21,619.78/cure and 40,573.33/cure, respectively. ICER was -$44,974.88/cure favoring daptomycin. Results from the one-way sensitivity analysis showed that duration of vancomycin intravenous treatment, cost of hospital night stay, and duration of daptomycin intravenous treatment were influential on the ICER; however, no break-even points were established and the model remained robust. Probabilistic sensitivity analysis displayed 77.9% of the ICER distribution in the dominant quadrant. Acceptability curve showed that daptomycin was ≥88.6% cost-effective compared to vancomycin at all ICER ranges. CONCLUSIONS Daptomycin was cost-effective compared to vancomycin due to decreased total direct cost and reduction in inpatient stay. As a result, the proportion of ICER in the probabilistic sensitivity analysis favored daptomycin 77.9% which was reflected in the acceptability curve.