Background: Resistant bacteria often complicate the management of skin and soft tissue infections of the lower extremities. This open-label study compared oral linezolid and intravenous vancomycin for management of complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods: Patients aged 18 years or older with proven MRSA-related complicated skin and soft-tissue infections requiring surgical intervention were randomized to receive oral linezolid (n = 30) or intravenous vancomycin (n = 30) for 7 to 21 days. Clinical and microbiological outcomes, duration of hospitalization and drug treatment, and outpatient charges were determined. Results: Linezolid was associated with greater rates of clinical cure and improvement (P = .015), a 3-day shorter median length of stay (P = .003), and reduced outpatient charges (P <.001). Vancomycin therapy was associated with more treatment failures and subsequent lower-extremity amputations (P = .011). Conclusions: Clinical outcomes were significantly better with linezolid than with vancomycin. Additionally, linezolid was associated with reduced length of stay and outpatient charges. (c) 2005 Excerpta Medica Inc. All rights reserved.