Background: Complicated skin and skin structure infections (cSSSIs) are a common reason for hospitalization. Inappropriate empiric therapy prolongs the hospital stay. Strategies that help clinicians target empiric therapy underlie antibiotic stewardship. We developed an algorithm to identify mixed (gram-positive+gram-negative organisms) cSSSI at hospital admission. Methods: We performed a retrospective cohort study at a single academic medical center among patients hospitalized from April 2006 to December 2007 with a cSSSI. Inappropriate empiric therapy was defined as failure to deliver an antibiotic with in vitro activity against the offending pathogen(s) within 24h of presentation. We derived a predictive rule to identify patients at risk for a mixed skin infection (MSI) and compared it with the "healthcare- associated" (HCA) definition. Results: Among 717 patients hospitalized with a cSSSI, 68 (9.5%) had an MSI, with 38.2% of these receiving inappropriate empiric therapy. Intensive care unit admission (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.12-5.52), infection other than an abscess (OR 2.01; 95% CI 1.06-3.81), and nursing home residence (OR 1.99; 95% CI 1.05-3.78) predicted MSI independently. The absence of all three factors identified non-MSI with 95.2% accuracy. The MSI rule improved the HCA classification accuracy for non-MSI by 21.9% without any loss in sensitivity. Conclusions: Hospitalization with an MSI is a risk factor for inappropriate empiric therapy. Intensive care unit admission, infection other than an abscess, and nursing home residence help identify those patients with a higher MSI risk. Absence of all these factors reliably identified patients not needing empiric MSI coverage. Relative to the HCA definition, the MSI rule resulted in the potential to prevent more than one in five additional patients from receiving unnecessarily broad empiric coverage.