Ventilator-associated pneumonia (VAP) is the most frequent occurring infection among mechanically ventilated patients. The clinical presentation of VAP ranges from relatively benign to a severe illness with septic shock. The influence of VAP on patient outcome has not been elucidated and its effects on the inflammatory response of the host are unknown. In a case-control study, the systemic inflammatory response was investigated in patients developing VAP as compared with control patients matched on duration of mechanical ventilation and underlying diseases. Patients developing VAP (n = 42) were matched to a single control (without VAP), who was matched on seven variables. VAP was diagnosed with bronchoscopic techniques. The inflammatory response, reflected by circulating levels of interleukin-6 (IL-6) and interleukin-8 (IL-8), was determined on the day of diagnosis (or day of matching for controls), 4 and 2 d before diagnosis, and 2 d after diagnosis. The development of VAP was not associated with an increase in circulating levels of IL-6 or IL-8. Among patients in which VAP was associated with a clinical presentation of severe sepsis or septic shock (n = 10), IL-6 and IL-8 levels increased and were higher than in the corresponding controls. Moreover, 60% of cases with severe sepsis or septic shock died as compared with 20% of their matched controls (p = 0.06). Mortality rates were similar in patients with uncomplicated VAP and their matched controls (25% and 34%, respectively). High circulating levels of IL-6 and IL-8 were associated with higher mortality rates. The clinical picture of VAP can be subdivided into different types, ranging from uncomplicated to an infection associated with severe sepsis or septic shock, elevated circulating levels of IL-6 and IL-8, and an increased mortality rate.