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Multidrug-resistant (MDR) strains of both Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) as causative ventilator-associated pneumonia (VAP) pathogens are becoming increasingly common. Still, the risk factors associated with this increased resistance have yet to be elucidated. The purpose of this study was to examine the changing sensitivity patterns of these pathogens over time and determine which risk factors predict MDR in trauma patients with VAP.Patients with either AB or PA VAP over 10 years were stratified by pathogen sensitivity (sensitive [SEN] and MDR), age, severity of shock, and injury severity. Prophylactic and empiric antibiotic days, risk factors for severe VAP, and mortality were compared. Multivariable logistic regression was performed to determine which risk factors were independent predictors of MDR.Three hundred ninety-seven patients were identified with AB or PA VAP. There were 173 episodes of AB (91 SEN and 82 MDR) and 224 episodes of PA (170 SEN and 54 MDR). The incidence of MDR VAP did not change over the study (p = 0.633). Groups were clinically similar with the exception of 24-hour transfusions (14 vs. 19 units, p = 0.009) and extremity Abbreviated Injury Scale (AIS) score (1 vs. 3, p < 0.001), both significantly increased in the MDR group. Antibiotic exposure as well as multiple episodes of inadequate empiric antibiotic therapy (mIEAT) (63% vs. 81%, p < 0.001) were significantly increased in the MDR group. Multivariable logistic regression identified prophylactic antibiotic days (odds ratio, 23.1; 95% confidence interval, 16.7–28, p < 0.001) and mIEAT (odds ratio, 18.1; 95% confidence interval, 12.2–26.1, p = 0.001) as independent predictors of MDR after adjusting for severity of shock, injury severity, severity of VAP, and antibiotic exposure.Prolonged exposure to unnecessary antibiotics remains one of the strongest predictors for the development of antibiotic resistance. Multivariable logistic regression identified prophylactic antibiotic days and mIEAT an independent risk factors for MDR VAP. Thus, limiting prophylactic antibiotic days is the only potentially modifiable risk factor for the development of MDR VAP in trauma patients.Level IV Therapeutic; level III Prognostic.