Purpose To describe the incidence and risk factors of methicillin sensitive Staphylococcus aureus ventilator associated pneumonia (MSSA-VAP) relapse in trauma and non-traumatic brain injury patients. Materials and methods Retrospective observational monocentric cohort study of consecutive ICU patients who developed a first episode of MSSA-VAP after trauma and non-traumatic brain injury. MSSA-VAP relapse encompass MSSA-VAP treatment failure (persistence or recurrence of MSSA) or other pathogen - VAP. Results A total of 165 patients (71% of trauma and 29% of non-traumatic brain injury) with MSSA-VAP were included. MSSA-VAP relapse occurred in 54 (33%) patients, including 28 (17%) MSSA-VAP treatment failure and 46 (28%) other pathogen-VAP. Empirical first-line antibiotic therapy was appropriate in 96% of cases. In multivariate analysis, the presence of Streptococcus species (Odds ratio [OR] 7.37) and oropharyngeal flora (OR 3.64) as initial MSSA co-pathogen, suggested aspiration at the time of admission and independently predicted MSSA-VAP treatment failure. Initial Glasgow coma scale (OR 0.89), need for emergent surgery (OR 5.71) and the presence of an acute respiratory distress syndrome at the time of the first MSSA-VAP (3.99), independently predicted the onset of other pathogen – VAP. Conclusion Early and simple factors may help to identify patients with high-risk of MSSA-VAP relapse.