OBJECTIVES: To determine the incremental cost-effectiveness of linezolid versus vancomycin using data from a clinical trial assessing treatment of nosocomial pneumonia due to MRSA in hospitalized adults. METHODS: A cost-effectiveness analysis from the U.S. hospital-payer perspective was piggybacked onto a phase 4, randomized, double-blind, multicenter trial (Wunderink et al, Clin Infect Dis 2012) in nosocomial pneumonia patients with culture-proven MRSA [microbiologic confirmed intent-to-treat (mITT) cohort]. Efficacy was measured by treatment success (defined as Cure+Improvement) at the end of study (i.e., 7-30 days after the end of treatment). Direct medical costs (USD, 2011 values) were calculated from the health care resources used, including study medication, hospitalization, mechanical ventilation, and dialysis. Nonparametric bootstrapping was conducted to calculate confidence intervals (CI) for costs, efficacy, and incremental cost-effectiveness ratios (ICER). One-way sensitivity analyses were conducted to evaluate the uncertainty and cost drivers. RESULTS: Data from 391 patients (186 linezolid, 205 vancomycin) were analyzed. A greater proportion of linezolid patients achieved treatment success vs. vancomycin patients [mean (95% CI)]: 55% (48.3%-61.9%) vs. 45% (38%-52.3%). Total costs per linezolid patient were $48,929 ($45,375-$52,483) compared to $46,665 ($43,201-$50,128) per vancomycin patient.  The point estimate for the ICER of linezolid vs. vancomycin was $16,516. The median ICER from bootstrapping was $16,219 (95% percentile: $100,487). Of the 10,000 bootstrap simulations, 73% had greater efficacies and higher costs (positive ICERs) for linezolid, 24% had greater efficacies and lower costs for linezolid (linezolid dominated vancomycin), and <2% had greater efficacies and lower costs for vancomycin (vancomycin dominated linezolid). Key cost drivers included number of ICU and general ward days in each treatment group. Addition of empirical treatment had a relatively small impact on ICER. CONCLUSIONS: In this clinical trial population, linezolid appears to be cost-effective compared to vancomycin in treating patients with nosocomial pneumonia due to MRSA.