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To evaluate whether one antibiotic achieves equal outcomes compared with combination antibiotic therapy in patients with Pseudomonas aeruginosa ventilator-associated pneumonia.A retrospective, multicenter, observational, cohort study.Five intensive care units in Spanish university hospitals.Adult patients identified to have monomicrobial episodes of ventilator-associated pneumonia with significant quantitative respiratory cultures for P. aeruginosa.None.A total of 183 episodes of monomicrobial P. aeruginosa ventilator-associated pneumonia were analyzed. Monotherapy alone was used empirically in 67 episodes, being significantly associated with inappropriate therapy (56.7% vs. 90.5%, p < .001). Hospital mortality was significantly higher in the 40 patients with inappropriate therapy compared with those at least on antibiotic with activity in vitro (72.5% vs. 23.1%, p < .05). Excess mortality associated with monotherapy was estimated to be 13.6% (95% confidence interval −2.6 to 29.9). The use of monotherapy or combination therapy in the definitive regimen did not influence mortality, length of stay, development of resistance to the definitive treatment, or appearance of recurrences. Inappropriate empirical therapy was associated with increased mortality (adjusted hazard ratio 1.85; 95% confidence interval 1.07–3.10; p = .02) in a Cox proportional hazard regression analysis, after adjustment for disease severity, but not effective monotherapy (adjusted hazard ratio 0.90; 95% confidence interval 0.50–1.63; p = .73) compared with effective combination therapy (adjusted hazard ratio 1). The other two variables also independently associated with mortality were age (adjusted hazard ratio 1.02; 95% confidence interval 1.01–1.04; p = .005) and chronic cardiac insufficiency (adjusted hazard ratio 1.90; 95% confidence interval 1.04–3.47; p = .035).Initial use of combination therapy significantly reduces the likelihood of inappropriate therapy, which is associated with higher risk of death. However, administration of only one effective antimicrobial or combination therapy provides similar outcomes, suggesting that switching to monotherapy once the susceptibility is documented is feasible and safe.