Intracranial pressure (ICP), cardiopulmonary function, and the degree of neurological dysfunction were measured in 13 patients with serious head injury to determine the relationship of these indices to the development of delayed pulmonary dysfunction. All patients had serious isolated head injury with Glasgow Coma Scale scores of 7 or less 6 hours after injury and elevated ICP at the time of admission to the protocol. Three patients developed arterial pO2 of less than or equal to 80 torr despite the initiation of elevated inspired oxygen fraction (FIO2 greater than or equal to 0.5) and positive end expiratory pressure (greater than or equal to 5 cm H2O. One of these three patients had a decline in neurological function, quantified by the Albany Head-Injury Watch Sheet, associated with hypoxemia. The only patients who developed intrapulmonary shunt fractions of more than 15% were five patients who had increased pulmonary vascular resistance (PVR) and elevated or increasing cardiac index, suggesting persistent perfusion to areas of the lung which normally are hypoperfused due to hypoxic pulmonary vasoconstriction. This mismatching of the distribution of ventilation and perfusion was confirmed using the multiple inert gas elimination technique in two patients with an increased shunt fraction. Unperfused gas exchange units were also found to be present, as confirmed by an abnormal multiple inert gas elimination techniques, high PVR and dead space/tidal volume ratio (VD/VT), and low extravascular lung water. Abnormalities of ICP and cerebral perfusion pressure could not be correlated with changes in any of the cardiopulmonary functions studied.