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Ventilator-associated pneumonia (VAP) is the most common infectious complication in the intensive care unit. It can increase duration of mechanical ventilation, length of stay, costs, and mortality. Improvements in the administration of empirical antibiotic therapy have potential to reduce the complications of VAP. This review will discuss the current data addressing empirical antibiotic therapy and the effect on mortality in patients with VAP. It will also address factors that could improve the administration of empirical antibiotics and directions for future research.