Background: Ventilator-associated pneumonia (VAP) caused by Stenotrophomonas maltophilia is poorly described in the literature. However, it has been shown to be associated with increased morbidity and mortality. Probabilistic antibiotic therapy against S. maltophilia is often ineffective as this pathogen is resistant to many antibiotics. There is no consensus at present on the best therapeutic strategy to adopt (class of antibiotics, antibiotic combination, dosage, treatment duration). The aim of this study was to evaluate the effect of antibiotic therapy strategy on the prognosis of patients with VAP caused by S. maltophilia. Results: This retrospective study evaluated all consecutive patients who developed VAP caused by S. maltophilia between 2010 and 2018 while hospitalized in the intensive care unit (ICU) of a French university hospital in Reunion Island, in the Indian Ocean region. A total of 130 patients with a median Simplified Acute Physiology Score II of 58 [43-73] had VAP caused by S. maltophilia after a median duration of mechanical ventilation of 12 [5-18] days. Ventilator-associated pneumonia was polymicrobial in 44.6% of cases, and ICU mortality was 50.0%. After multivariate Cox regression analysis, the factors associated with increased ICU mortality were older age (hazard ratio (HR): 1.03; 95% CI 1.01-1.04, p = 0.001) and high Sequential Organ Failure Assessment score on the day of VAP onset (HR: 1.08; 95% CI 1.03-1.14, p = 0.002). Appropriate antibiotic therapy, and in particular trimethoprim-sulfamethoxazole, was associated with decreased ICU mortality (HR: 0.42; 95% CI 0.24-0.74, p = 0.003) and decreased hospital mortality (HR: 0.47; 95% CI 0.28-0.79, p = 0.04). Time to start of appropriate antibiotic therapy, combination therapy, and duration of appropriate antibiotic therapy had no effect on ICU mortality (p > 0.5). Conclusion: In our study, appropriate antibiotic therapy, and in particular trimethoprim-sulfamethoxazole, was associated with decreased ICU and hospital mortality in patients with VAP caused by S. maltophilia.