Abstract Background Complicated skin and soft tissue infections (cSSTIs) occur frequently, but limited data do not allow any consensus on an optimal treatment strategy. We designed this prospective, multicenter, observational study to to explore the current epidemiology, treatment, and resulting clinical outcomes of cSSTIs to help develop strategies to potentially improve outcomes. Methods From June 2008 to December 2009 we enrolled a pre-specified number of adults treated in 56 U.S. hospitals with intravenous antibiotic(s) for any of the following cSSTIs: diabetic foot infection (DFI); surgical site infection (SSI); deep soft tissue abscess (DSTA); or, cellulitis. Investigators treated all patients per their usual practice during the study and collected data on a standardized form. Results We enrolled 1,033 patients (DFI 27%; SSI 32%; DSTA 14%; cellulitis 27%; mean age 54 years; 54% male), of which 74% had healthcare-associated risk factors. At presentation, 89% of patients received initial empiric therapy with intravenous antibiotics; ~20% of these patients had this empiric regimen changed or discontinued based on culture and sensitivity results. Vancomycin was the most frequently used initial intravenous antibiotic, ordered in 61% of cases. During their stay 44% of patients underwent a surgical procedure related to the study infection, usually incision and drainage or debridement. The mean length of stay was 7.1 days, ranging from 5.8 (DSTA) to 8.1 (SSI). Conclusion Our findings from this large prospective observational study that characterized patients with cSSTIs from diverse US inpatient populations provide useful information on the current epidemiology, clinical management practices and outcomes of this common infection.