Background: Early-onset ventilator-associated pneumonia (EO-VAP) is the leading cause of morbidity and mortality in comatose patients. However, VAP prevention bundles focus mainly on late-onset VAP and may be less efective in preventing EO-VAP in comatose patients. Systemic antibiotic administration at the time of intubation may have a role in preventing EO-VAP. Therefore, we evaluated the efectiveness of systemic antibiotic administration in VAP prevention in comatose patients through a systematic review and meta-analysis. Methods: We searched for studies published through December 2015 that evaluated systemic antibiotic prophylaxis in comatose patients. Two authors independently selected and evaluated full-length reports of randomized clinical trials or prospective cohorts in patients aged >16 years that evaluated the impact of systemic antibiotics at the time of intubation on EO-VAP compared to placebo or no prophylaxis. The outcome variables were the incidence of EOVAP, the duration of mechanical ventilation, ICU length of stay, and ICU mortality. Results: We identifed 10,988 citations, yielding 26 articles for further analysis; three studies with 267 patients were fnally analyzed. Most patients (n = 135) were comatose due to head trauma. Systemic antibiotic administration was associated with decreased incidence of EO-VAP (RR 0.32; 95% CI 0.19–0.54) and shorter ICU LOS (standardized mean diference −0.32; 95% CI −0.56 to −0.08), but had no efect on mortality (RR 1.03; 95% CI 0.7–1.53) or duration of mechanical ventilation (standardized mean diference −0.16; 95% CI −0.41 to 0.08). Conclusions: Antibiotic prophylaxis in comatose patients reduced the incidence of EO-VAP and decreased the ICU stay slightly. Future trials are needed to confrm these results.