OBJECTIVES: Vancomycin is often considered first-line for complicated gram+ infections; however, a rise in resistant infections in both hospital and community settings may impact efficacy and total cost of treatment. Our objective was to systematically evaluate the clinical efficacy and resource use/economic characteristics of vancomycin in recent randomized clinical trials (RCT) or economic studies for treatment of complicated gram+ infections, such as skin and soft tissue infections (SSTI), including methicillin-resistant staphylococcus aureus (MRSA). METHODS: A literature search was conducted in PubMed, EMBASE, IPA, and infectious disease abstract databases to identify clinical or economic studies of vancomycin published from 2000-2006. Clinical outcomes data were synthesized by study design, infection type, MRSA status, intent to treat (ITT) efficacy, microbiologic cure, MRSA efficacy, and adverse events (AEs). Efficacy data were pooled when possible. Economic data abstracted included hospital length of stay (LOS), length of treatment (LOT), and cost of treatment (COT) adjusted to 2006 US$. RESULTS: Twelve studies (including 5 RCTs with 4 in SSTI) were identified reporting specific clinical efficacy outcomes and/or economic data. The ITT average efficacy (range) for vancomycin 1gm IV q12hr for SSTIs was 85% (76.9-88.5%) and microbiologic cure was 89% (77-97.6%). For MRSA SSTIs, efficacy was lower at 68% (50-81%). Incidence of drug-related AEs was 3.6-20.6%, and drug-related discontinuations 4.5-5.8%. Hospital LOS ranged from 8-15 days, and LOT 9-11 days. Resistance increased COT, with an MRSA SSTI incurring at least 2-3 more days for LOS and total COT > $23,000. CONCLUSION: Vancomycin's clinical and economic efficiency may be reduced for patients with complicated MRSA SSTIs. The level of antibiotic resistance should be factored into comparative economic analyses of vancomycin and new treatments for gram+ infections.