OBJECTIVES: To derive the frequency and costs associated with failure of initial mupirocin therapy among patients diagnosed with uncomplicated skin and skin structure infections (uSSSI). METHODS: A retrospective observational analysis was conducted using data obtained from the Integrated Healthcare Information Systems (IHCIS) dataset which contains nationally representative managed care claims data. This analysis utilized medical, pharmacy, and enrollment records between January 1, 2003 and April 30, 2006. Patients with a mupirocin prescription and a corresponding ICD9 code for an uSSSI up to 15 days prior to their index mupirocin prescription were eligible for the analysis. A patient was classified as failing treatment with mupirocin if they either: 1) received a second antibiotic commonly used to treat uSSSI 5 – 30 days after their index mupirocin prescription or 2) experienced an uSSSI-related hospitalization within 30 days after the index mupirocin prescription. Among those patients that were defined as mupirocin failures the frequency and costs (2005 US dollars) of a second uSSSI antibiotic, outpatient encounter, and hospitalization was derived. RESULTS: A total of 160,445 mupirocin prescriptions associated with an uSSSI were dispensed during the study timeframe. Of those prescriptions 12,650 (7.0%) resulted in failure. Among failures 93.8% (11,867) required a second antibiotic contributing a mean cost of $62 per prescription. Outpatient encounters were required by 40.3% (4,782) of failures with a mean cost of $221 per encounter. Only 9.0% of failures required a hospitalization, but resulted in a mean cost of $6,597 per hospitalization. This translates into an expected cost of $740.95 per mupirocin failure among uSSSI patients. CONCLUSION: The management of uSSSI is costly when initial pharmacologic therapy fails.