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Background: Is there an advantage of volume-controlled ventilation (VCV) over pressure-controlled ventilation (PCV) in the management of patients with intracranial pathology? Methods: Between August 2015 and March 2017, a prospective monocentric crossover trial was performed in neurocritical care patients with invasive ICP monitoring and mechanically controlled ventilation. Two different ventilation modes (VCV and PCV) were applied during a night shift for two hours in each intervention group. The primary end point was the dispersion of ICP and CPP. Secondary endpoints included the differences between mean ICP and CPP, and the incidence of critical ICP or CPP values (ICP > 20 mmHg, CPP < 50 mmHg).Results: Data from a total of 32 patients were analysed. VCV was associated with increased dispersion of maximum ventilation pressure. PCV resulted in elevated dispersion of minute volume and tidal volume. Differences in the dispersion of ventilation parameters did not result in increased dispersion of ICP and CPP. However, we found a significant decrease in mean CPP values with VCV (76.2 mmHg versus 80.1 mmHg; p = 0.03). Furthermore, VCV was associated with a significantly increased rate of adverse events with a CPP < 50 mmHg (VCV: 4.4% versus PCV: 2.6%, p = 0.03). Conclusions: In our study population, VCV was not superior to PCV with regard to ICP and CPP. Moreover, our data suggest that PCV may lead to higher CPP values and may reduce the rate of decreased CPP in patients with acute brain diseases. Trial registration: German trial register (ID: DRKS00009832; date of registration: 30/12/2015; website: www.germanctr.de).