Opioids are routinely used to provide analgesia in mechanically ventilated patients. Opioid use is associated with increased risk of ICU-acquired infection, particularly VAP. Prolongation of exposure to mechanical ventilation, microaspiration, gastrointestinal motility disturbances, and immunomodulatory effects are the potential mechanisms by which opioids may favour VAP in these patients. Activation of sympathic nervous system, and hypothalamic-pituitaryadrenal axis was identified after morphine withdrawal. In addition, suppression of mitogen-stimulated proliferation of T and B-lymphocytes, natural killer activity, antibody production, IL2, IL12, INFγ, and NO production are the main immune effects observed during acute and chronic morphine exposure. The use of short acting opioids is associated with shorter duration of mechanical ventilation and ICU stay, and might be helpful in preventing VAP. Future studies should compare the effect of different opioid agents, and the impact of progressive opioid discontinuation compared with abrupt discontinuation on VAP incidence.