Patients with nosocomial pneumonia have evidence of immunosuppression. The most obvious defect in immunity is the loss of mechanical barriers with an endotracheal tube. Only a third of colonized patients on ventilators develop pneumonia, however, suggesting that altered immunity is more extensive. This subgroup of patients tends to get multiple synchronous and sequential infections. The exact mechanisms of this compromise of immunity remain to be fully elucidated. Both a temporary immunocompromised and a specifically predisposed subpopulation, however, can explain the clinical pattern. A temporary immunoparalysis clearly occurs and is associated with increased risk of infections. An underlying genetic predisposition may lead to a predisposed population. Genetic polymorphisms in pathogen recognition molecules increase the risk of nosocomial infections. Genetic variability in immune mediators increase severity of infections and mortality but have not been demonstrated as consistently to lead to infections. Adequate treatment of an initial infection is required for reversal of the temporary immunoparalysis, whereas specific immunomodulatory therapies can reverse the markers of immunoparalysis and may decrease the risk of infection.