The pathogenicity of late respiratory infections with herpes simplex virus type 1 (HSV-1) in the critically ill is unclear. In four critically ill patients with persistent pulmonary infiltrates of unknown origin and isolation of HSV-1 from tracheal aspirate or bronchoalveolar lavage fluid, at 7 (1-11) days after start of mechanical ventilatory support, a pulmonary leak index (PLI) for 67Gallium (67Ga)-transferrin (upper limit of normal 14.1 x 10(-3)/min) was measured. The PLI ranged between 7.5 and 14.0 x 10(-3)/min in the study patients. Two patients received a course of acyclovir and all survived. The normal capillary permeability observed in the lungs argues against pathogenicity of HSV-1 in the critically ill, and favors that isolation of the virus reflects reactivation in the course of serious illness and immunodepresssion, rather than primary or superimposed infection in the lungs.