Gram-positive organisms are emerging as possibly the most important nosocomial pathogens during the past decade. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of infection in the postoperative patient. Burn victims are at high risk for developing vancomycin-resistant Enterococcus (VRE) and other multidrug-resistant microbial infections as a result of the immunocompromising effects of burn injury, prolonged intensive care unit stays, and broad-spectrum antibiotic therapy. To prevent serious and dreaded complications such as skin graft breakdown, delayed wound healing, loss of a limb, and even death, these infections require a combination of extensive antibiotic therapy and plastic surgical intervention. The objectives of this study were to report clinical experience with linezolid in addition to wound care, debridement, and wound coverage techniques for the treatment of S. aureus (including MRSA) and VRE infections. Forty patients received linezolid for infections of wound coverage such as an infected graft or flap, or received linezolid in conjunction with wound coverage techniques for a S. aureus or VRE infection. The median patient age was 53 years (range, 14-85 years), 55% were female, 28% of patients received intravenous (i.v.) linezolid only, 45% received i.v. with a switch to the oral formulation, and 28% received the oral formulation only. The clinical success rate of linezolid with adjuvant wound coverage techniques was 90.0% for osteomyelitis and was 100% for skin and soft-tissue infections. For infections of wound coverage, the clinical success rate was 83.3%. In conclusion, linezolid was an effective antibiotic for the treatment of S. aureus (including MRSA) and VRE infections in conjunction with wound coverage techniques. In addition, linezolid offers the option of treating these infections with an oral agent that is 100% bioavailable.