Objective: We investigated the effect of cerebrospinal fluid (CSF) drainage on the intracranial pressure (ICP) signal measured in the parenchyma and the ventricle as well as the effect on the pressure reactivity index (PRx) calculated from both signals. Methods: Ten patients were included in this prospective study. All patients received a parenchymal ICP sensor and an external ventricular drain (EVD) for CSF drainage. ICP signals (ICP-p and ICP-evd) were captured. Part of the study was a period of 90 min during which the patient was free from any manipulation, consisting of 30 min of drainage (O1), 30 min EVD closed (C) and 30 min of drainage (O2). Results: Mean ICP-evd and mean AMP-evd increased (3.03 and 0.46 mmHg) from O1 to C and decreased (2.12 and 0.43 mmHg) from C to O2. ICP-p and AMP-p changes were less pronounced (closing EVD: +0.81 mmHg/+0.22 mmHg; opening EVD: −0.22 mmHg/−0.05 mmHg). Mean difference between PRx-evd and PRx-p was 0.12 for O1, 0.02 for C and −0.02 for O2. The intraclass correlation coefficient for absolute agreement of single measures was 0.66 for O1, 0.77 for C and 0.69 for O2. Mean PRx differences demonstrated a significant difference between O1 versus C and O1 versus O2 but not between C versus O2. Conclusion: Drainage of CSF reduces ICP magnitude and amplitude through the EVD. This effect was only marginal in parenchymal ICP measurements. In manipulation-free circumstances, agreement of PRx obtained through parenchymal and ventricular measurements was moderate to good, depending on the statistical method, and was not necessarily influenced by drainage.