In traumatic brain injury, the hypocapnic effects on blood pressure autoregulation may vary from beneficial to detrimental. The consequences of moderate hypocapnia (HC) on the autoregulation of cerebral perfusion pressure (CPP) have not been monitored so far. Thirty head injured patients requiring sedation and mechanical ventilation were studied during normocapnia (5.1 ± 0.4 kPa) and moderate HC (4.4 ± 3.0 kPa). Transcranial Doppler flow velocity (Fv) of the middle cerebral arteries (MCA), invasive arterial blood pressure, and intracranial pressure were monitored. CPP was calculated. The responsiveness of Fv to slow oscillations in CPP was assessed by means of the moving correlation coefficient, the Mx autoregulatory index. Hypocapnic effects on Mx were increasing with its deviation from normal baseline (left MCA: R 2 = 0.67; right MCA: R 2 = 0.51; p < 0.05). Mx indicating normal autoregulation (left:-0.23 ± 0.23; right:-0.21 ± 0.24) was not significantly changed by moderate HC. Impaired Mx autoregulation, however, (left: 0.37 ± 0.13; right: 0.33 ± 0.26) was improved (left: 0.12 ± 0.25; right:-0.0003 ± 0.19; p < 0.01) during moderate HC. Mx was adjusted to normal despite no significant change in CPP levels. Our study showed that short-term moderate HC may optimize the autoregulatory response to spontaneous CPP fluctuations with only a small CPP increase. Patients with impaired autoregulation seemed to benefit the most.