Background:Retrospective studies have reported good clinical success rates using colistin as monotherapy to treat Acinetobacter baumannii ventilator-associated pneumonia (VAP), comparable to that obtained with colistin combined with other antibiotics. However, inadequate penetration into the pulmonary parenchyma for colistin has been shown in animal models.Aim:The aim of the study was to study prospectively the outcome, measured as clinical response and survival, of intravenously administered colistin versus colistin combined with high-dose ampicillin-sulbactam in Intensive Care Unit (ICU) patients with multiresistant A. baumannii VAP.Methods and Subjects:This prospective, open-label, randomized study included consecutive patients who developed microbiologically documented VAP due to A. baumannii with carbapenem-resistant strains but susceptible to colistin and ampicillin-sulbactam. Seventy-four patients were screened, but finally, 39 participants were enrolled and finished the study Patients received colistin (Group A – 19 patients) or colistin and ampicillin/sulbactam (Group B – 20 patients). The clinical response of VAP was assessed on day 4th to 5th of treatment (early response). If therapy was considered unsuccessful after this period, ampicillin/sulbactam was added in Group A or changed therapy in B.Results:Early cure rates in Group A and B were 15.8% and 70%, respectively (P = 0.001). Multiple regression analysis revealed that combination treatment (odds ratio [OR]: 43.6, 95% confidence interval [CI]: 3.594–530.9) and Sequential Organ Failure Assessment score <8 (OR: 0.022, 95% CI: 0.001–0.43) were independently associated with favorable clinical response. APACHE II score ≤15 (OR: 0.049, 95% CI: 0.003–0.0942) and an early favorable response to treatment (OR: 244.4, 95% CI: 2.151–27850.9) were associated with survival and discharge from ICU.Conclusion:Combination therapy with colistin and a high dose of ampicillin/sulbactam was associated with a more favorable clinical response to VAP due to carbapenem-resistant A. baumannii than colistin monotherapy.