OBJECTIVES: Complicated skin and skin structure infections (cSSSIs) are a common complication among hospitalized patients. There are limited national data on the costs of cSSSIs due to Staphylococcus aureus, a common hospital-acquired pathogen. METHODS: This retrospective cohort study used data from the 2004 Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS). Patients with S. aureus cSSSIs were identified based on ICD-9-CM diagnosis codes and compared to patients without skin infections. Excess mortality, length of stay (LOS), and costs were estimated for both groups. Multivariate models (with log transformation) were used to adjust costs for potential confounding factors, including age, gender, mortality, hospital region, and comorbidity. RESULTS: We identified 55,585 hospitalized patients with cSSSIs due to S. aureus. The comparison cohort consisted of 7,618,776 patients without skin infections. The mortality rates were similar for the S. aureus cSSSI and comparison cohorts (3.9% and 2.0%, respectively). For comparison purposes, the mortality rate of all inpatients with S. aureus infections was 7.3%. Patients with S. aureus cSSSIs were older (mean age 54 years vs. 46 years for the comparison group) and were more likely to have congestive heart failure, diabetes with chronic complications and bacteremia/septicemia. Relative to the comparison group, patients with S. aureus cSSSIs had significantly (P<.0001) longer mean length of stay (9.7 vs. 4.4 days) and higher average costs per stay ($16,941 vs. $9,154). After controlling for potentially confounding factors, the excess mean costs associated with S. aureus cSSSIs were estimated to be $3,396. CONCLUSION: Our findings suggest that the clinical and economic burden of complicated skin and skin structure infections (cSSSIs) due to Staphylococcus aureus among hospitalized patients is substantial.