OBJECTIVE: To determine the effectiveness of oral decontamination with 2% chlorhexidine solution for the prevention of ventilator-associated pneumonia (VAP). DESIGN: Randomized controlled trial and meta-analysis. SETTING: A tertiary care university hospital in Bangkok, Thailand. PARTICIPANTS: Adult patients who received mechanical ventilation and who were hospitalized in intensive care units and general medical wards. METHODS: The patients were randomized to receive oral decontamination with 2% chlorhexidine solution or normal saline solution 4 times per day until their endotracheal tubes were removed. The outcome measures were the development of VAP and oropharyngeal colonization with gram-negative bacilli. Meta-analysis was performed by combining the results of the present study with those from another randomized controlled trial that also used a 2% chlorhexidine formulation for oral decontamination. RESULTS: The characteristics of the patients in the chlorhexidine group (n=102) and the normal saline group (n=105) were not significantly different. The incidence of VAP in the chlorhexidine group was 4.9% (5 of 102), and the incidence in the normal saline group was 11.4% (12 of 105) (P=.08). The rate of VAP in the chlorhexidine group was 7 episodes per 1,000 ventilator-days, and the rate in the normal saline group was 21 episodes per 1,000 ventilator-days (P=.04). Irritation of the oral mucosa was observed in 10 (9.8%) of the patients in the chlorhexidine group and in 1 (0.9%) of the patients in the normal saline group (P=.001). Oropharyngeal colonization with gram-negative bacilli was either reduced or delayed in the chlorhexidine group. Overall mortality of the patients did not differ significantly between the groups. Meta-analysis of 2 randomized controlled trials revealed an overall relative risk of VAP for patients in the chlorhexidine group of 0.53 (95% confidence interval, 0.31-0.90; P=.02). CONCLUSION: Oral decontamination with 2% chlorhexidine solution is an effective and safe method for preventing VAP in patients who receive mechanical ventilation.