Background: Comatose patients present a high risk of early-onset ventilator-associated pneumonia (EO-VAP) for which antibiotic prophylaxis has been proposed. Comatose patients were studied to evaluate the efficacy of a single-dose of antibiotic prophylaxis at intubation against EO-VAP. Methods: A prospective cohort of comatose patients (Glasgow Coma Score ≤8) who were admitted in 2009-2010 and administered a single-dose of antibiotic within 4 h of intubation was compared with comatose patients (admitted ≥4 h after intubation in 2009-2010 or admitted in 2007-2008) who did not receive antibiotic prophylaxis. We analyzed the incidence of EO-VAP, late-onset VAP, and ventilator-associated tracheobronchitis in both groups. Propensity scores for receiving antibiotic prophylaxis were derived on the basis of patients' characteristics (eg, age and severity) to assess its impact on EO-VAP development. Results: We included 129 patients (71 in the prophylaxis group and 58 in the control group). The global incidence of VAP and incidence of EO-VAP were lower in the prophylaxis group:10.8 vs 28.4 episodes/1,000 days on mechanical ventilation (P = .015) and 4.4 vs 23.1 episodes/1,000 days on mechanical ventilation (P = .02), respectively. The incidence of late-onset VAP did not differ. The prophylaxis group tended toward lower incidence of ventilator-associated tracheobronchitis (15.5% vs 25.9%, P = .14). No differences in mortality were found between groups. The propensity- score regression analysis confirmed that a single dose of antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11;95% CI, 0.02-0.58;P = .009). Conclusions: A single dose of antibiotic prophylaxis at intubation might lower the incidence of EO-VAP. However, a randomized clinical trial should be conducted to confirm our findings. © 2013 American College of Chest Physicians.