OBJECTIVES: Current guidelines for the treatment of acute bacterial skin and skin structure infections (ABSSSI) recommend treatment pathways based on the infection types and severity. However, few studies have attempted to establish the healthcare resource utilization and costs overall and in various treatment settings, e.g., ED visits, in-patient, outpatient visit and/or treatment (e.g. infusion center), and outpatient pharmacy, using real world data. METHODS: The medical and pharmacy administrative claims of adult ABSSSI subjects with continuous commercial or Medicare Advantage enrollment with Part D prescription drug coverage (MAPD) between 01 January 2009 and 31 December 2011 were extracted from a large national health plan affiliated with OptumInsight. Subjects were grouped based on their initiation of five MRSA-active antibiotics: linezolid, vancomycin, daptomycin, clindamycin, or tigecycline. Healthcare resource utilization and costs were assessed for each treatment group. RESULTS: After applying inclusion and exclusion criteria, 8,332 commercial and 4,218 MAPD were included in the study.  The average age was 50 years for commercial enrollees and 69 years for MAPD enrollees. The Quan-Charlson comorbidity index varied among treatment groups and, a majority of the clindamycin treatment subjects had few or no comorbidities. The average ABSSSI-related total health care cost, per patient per month, was $18,290 including $7,261(39.7%) for inpatient cost, $825(4.5%) for ED visits, $2,447 (13.4%) for outpatient treatment/visits, $1233(6.7%) for pharmacy claims, $971(5.3%) for office visits, and $5553 (30.4%) for other medical cost. The costs overall and in various treatment settings varied by initial antibiotic choices and insurance plans. CONCLUSIONS: Inpatient treatment remains the largest component of total ABSSSI treatment cost. To minimize the burden on the healthcare system, there is an urgent need to develop new antibiotics that prevent or decrease the number of hospitalizations and reduce the length of inpatient stays.