Previous studies suggest a relationship between hyperoxemia and ventilator-associated pneumonia (VAP). Hyperoxemia is responsible for denitrogenation phenomena, and inhibition of surfactant production, promoting atelectasis in mechanically ventilated patients. Further, hyperoxemia impairs the efficacy of alveolar macrophages to migrate, phagocyte and kill bacteria. Oxygen can also cause pulmonaryspecific toxic effect called hyperoxic acute lung injury leading to longer duration of mechanical ventilation.All these hyperoxic effects are well-known risk factors for VAP. A recent retrospective large single center study identified hyperoxemia as an independent risk factor for VAP. However, two recent randomized controlled trials evaluated the impact of conservative oxygen strategy versus a liberal strategy, but did not confirm the role of hyperoxemia in lower respiratory tract infection occurrence. In this review, we discuss animal and human studies suggesting a relationship between these two common conditions in mechanically ventilated patients and potential interventions that should be evaluated. Further large prospective studies in carefully selected groups of patients are required to confirm the potential role of hyperoxemia in VAP pathogenesis and to evaluate the impact of a conservative oxygen strategy vs. a conventional strategy on the incidence of VAP.