We present the case reports of two patients with severe traumatic brain injury who, in the absence of external stimuli, developed episodes of acute elevation of intracranial pressure (plateau waves) associated with jugular bulb oxyhemoglobin (SjO2) desaturation, severe reduction of cerebral tissue PO2 (PbrO2), and deterioration of neurological status. In all of these episodes hyperventilation was successful in extinguishing plateau waves, but in one patient it was associated with an improvement of both the global (increased SjO2) and local (increased PbrO2) cerebral perfusion, while in the other patient it was associated with a reduction of both SjO2 and PbrO2. In both patients the effects of hyperventilation (and other pharmacological treatments) were short-lived; plateau waves reappeared and the patients had to be submitted to decompressive craniotomy (first patient) and cerebrospinal fluid (CSF) drainage (second patient). We conclude that hyperventilation can be useful as a temporary measure to treat plateau waves, but cerebral oxygenation should always be monitored to avoid iatrogenic cerebral ischemia.