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Objective: Inappropriate empiric therapy worsens outcomes in certain healthcare-associated infections (HCAI). We studied the association of inappropriate empiric therapy with outcomes in patients with HCA complicated skin and skin structure infections (cSSSI)., Design: A single-center retrospective cohort study., Patients: Hospitalized with a culture-positive cSSSI., Measurements: We defined HCA-cSSSI as having ≥1 of these risk factors: (1) recent hospitalization, (2) recent antibiotics, (3) hemodialysis, (4) transfer from a nursing home, and inappropriate treatment as no antimicrobial therapy active against the pathogen(s) within 24 hours of obtaining culture specimen. We performed descriptive and multivariate statistics to compute the impact of inappropriate empiric therapy on outcomes. Hospital length of stay (LOS) served as primary and mortality as secondary outcomes., Results: Of the 717 patients with culture-positive cSSSI, 527 (73.5%) had HCAI, of whom 405 (76.9%) received appropriate treatment. A higher proportion of those receiving inappropriate than appropriate treatment had a decubitus ulcer (29.5% vs. 10.9%, P < 0.001), a device-associated infection (42.6% vs. 28.6%, P = 0.004), or bacteremia (68.9% vs. 57.8%, P = 0.028). The frequency of methicillin-resistant Staphylococcus aureus (MRSA) did not differ between the groups. The low overall unadjusted mortality rate did not vary based on initial treatment. In a multivariable analysis adjusting for potential confounders inappropriate therapy had an attributable increase in hospital LOS of 1.8 days (95% CI, 1.4-2.3)., Conclusion: Similar to other populations with HCAI, HCA-cSSSI patients are likely to receive inappropriate empiric therapy for their infection. This early exposure is associated with a significant prolongation of the hospitalization by nearly 2 days., (Copyright © 2010 Society of Hospital Medicine.)