Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of ventilator-associated pneumonia (VAP). This prospective, open-label, multicenter clinical trial compared the early microbiological efficacy of linezolid (LZD) therapy with that of vancomycin (VAN) therapy in patients with MRSA VAP. A total of 149 patients with suspected MRSA VAP were randomized to receive either LZD, 600 mg, or VAN, 1 g every 12 h. Patients with baseline bronchoscopic BAL (BBAL) fluid quantitative culture findings that were positive for MRSA (≥ 104 cfu/mL) comprised the study population. The primary outcome was microbiological response (≤ 102 cfu/mL) in a second BBAL performed 72 to 96 h following the start of treatment. Thirty LZD-treated patients and 20 VAN-treated patients had microbiologically confirmed MRSA at baseline; 23 and 19 patients, respectively, underwent repeat BBAL. While a greater number of LZD-treated patients than VAN-treated patients achieved a microbiological cure (56.5% vs 47.4%, respectively; p = 0.757; 95% confidence interval, −21.1 to 39.4), this difference was not statistically significant. Nonstatistically significant differences were also seen for LZD-treated patients vs VAN-treated patients in terms of clinical cure (66.7% vs 52.9%, respectively), survival rate (86.7% vs 70.0%, respectively), and the mean duration of ventilation (10.4 vs 14.3 d, respectively), hospitalization (18.8 vs 20.1 d, respectively), ICU stay (12.2 vs 16.2 d, respectively), and time spent alive and not receiving mechanical ventilation (15.5 vs 11.1 d, respectively). Three patients who had been extubated prior to undergoing repeat BBAL had been randomized to receive LZD therapy. Early microbiological cure rates were not statistically significantly higher with LZD therapy than with VAN therapy despite trends in all secondary clinical outcomes favoring LZD therapy. These results suggest that any beneficial effect of LZD therapy may be due to factors other than increased bacterial clearance. Clinicaltrials.gov Identifier: NCT00572559