Rationale: It is not known whether the isolation of herpes simplex virus (HSV) from lower respiratory tract samples of nonimmunocompromised ventilated patients corresponds to bronchial contamination from the mouth and/or throat, local tracheobronchial excretion of HSV, or true HSV lung involvement (bronchopneumonitis) with its own morbidity/mortality. Objective: This prospective, single center, observational study was conducted to define the frequency, risk factors and relevance of HSV bronchopneumonitis. Methods: All consecutive nonimmunocompromised patients receiving mechanical ventilation for 5 days were evaluated. Bronchoalveolar lavage, oropharyngeal swabs and bronchial biopsies (presence of macroscopic bronchial lesions) were obtained for all who deteriorated clinically with suspected lung infection. HSV bronchopneumonitis was defined as this deterioration, associated with HSV in bronchoalveolar lavage and HSV-specific nuclear inclusions in cells recovered during lavage or bronchial biopsies. Measurements and Main Results: HSV bronchopneumonitis was diagnosed in 42 (21%) of the 201 patients who deteriorated clinically, with a mean mechanical ventilation duration before diagnosis of 14 ± 6 days. Risk factors associated with HSV bronchopneumonitis were oral-labial lesions, HSV in throat and macroscopic bronchial lesions seen during bronchoscopy. Patients with HSV bronchopneumonitis were comparable to those without at admission, but their courses were more complicated, with longer duration of mechanical ventilation and ICU stays. Conclusions: HSV bronchopneumonitis is common in nonimmunocompromised patients with prolonged mechanical ventilation, is associated with HSV reactivation or infection of the mouth and/or throat and seems to be associated with poorer outcome.