To investigate the role of ventilation-perfusion (VA/Q) imbalance in the hypoxemia observed after head injury, 5 male subjects (17 to 26 years of age) with isolated head trauma and subsequent hypoxemia were studied. Disturbances of ventilation and perfusion were assessed using the steady-state elimination of six inert gases of different solubilities. Paired studies were conducted during mechanical ventilation with a volume-cycled ventilator and during spontaneous ventilation. Distributions recovered from studies of spontaneous ventilation show a mode of ventilation and perfusion near a VA/Q of 1.0. In addition, 41% of the cardiac output was distributed to a second population of lung units with low VA/Q (less than 0.1) and shunt. During mechanical ventilation, perfusion to these regions of low VA/Q decreased to 21% of the cardiac output, whereas shunt fraction was unchanged. This was associated with a marked broadening of the VA/Q mode near 1.0, relative to the studies during spontaneous ventilation. Mean functional residual capacity during mechanical ventilation was not different from that during spontaneous ventilation. These results suggest that head injury can lead to hypoxemia through a failure of VA/Q regulatory mechanisms.