Background and Purpose: Ventilator-associated pneumonia (VAP) is an important nosocomial infection worldwide, which leads to increased length of hospital stay, healthcare costs and mortality. Evidence on oral decontamination with antiseptic in reducing VAP is limited. Hence, a meta-analysis was performed to determine the effect of chlorhexidine oral decontamination in the reduction of VAP in mechanically ventilated patients Methods: An extensive literaturereview was conducted using the following databases: CINAHL, MEDLINE, Joanna Briggs Institute, Cochrane Library, EMBASE, CENTRAL, and the Google search engine. Retrieved articles were selected based on the methodological quality, inclusion criteria and analysed to find the pooled effect size. Results: The nine trials included in this meta-analysis revealed a significant reduction in the incidence of VAP among patients who received prophylactic oral decontamination with Chlorhexidine. However no significant effect was found in reducing overall mortality rate among the mechanically ventilated patients. Conclusion: The safety profile regarding the possible selection and induction of antibiotic resistance and presumed cost benefits of Chlorhexidine make it a highly attractive intervention for the prevention of VAP. This meta-analysis indicated that chlorhexidine can serve as a cost-effective and safe antiseptic in preventing VAP in mechanically ventilated patients. © 2012 Elsevier B.V., All rights reserved.