OBJECTIVES: Complicated skin and skin structure infections (cSSSI) are a common reason for hospitalization. Inappropriate empiric therapy (IAET) for cSSSI prolongs hospital stay. Patients with a mixed cSSSI (MSI, gram positives [GP] and gram negatives [GM] present) are at an increased risk for receiving IAET. We set out to examine the bacteriology and components of IAET coverage in MSI. METHODS: We conducted a single-center retrospective cohort study of patients hospitalized April 2006 to December 2007 with a cSSSI. IAET was defined as failure to deliver an antibiotic with in vitro activity against the offending pathogen(s) within 24 hours of presentation.   RESULTS: Of the 717 patients hospitalized with a cSSSI, 158 (22%) received IAET; 68 (9.5%) had a MSI. Among all MSI, most frequently isolated pathogens were methicillin-resistant S. aureus (MRSA) (n=23, 33.8%), Streptococcus sp. (n=22, 32.4%) and P. aeruginosa (n=21, 30.9%). IAET was noted in 26 (38.2%) MSIs. Both appropriate GP and GN coverage were missing in 7 (26.9%) cases. While among all MSIs treated with IAET Streptococcus sp. coverage was never missing, treatment for MRSA was absent in 3 (11.5%) cases. Most frequently missing coverage was for GN (n=18, 69.2%), with P. aeruginosa untreated in 6 (23.1%). GP coverage was absent in 15 (57.7%), most frequently for vancomycin-resistant Enterococcus sp. (VRE) (n=9, 34.6%).   CONCLUSIONS: In this single-center study, patients with a MSI were at high risk for IAET. Coverage was more frequently left out for GN than for GP, with P. aeruginosa and VRE frequently remaining untreated empirically.