In recent years, the measurement of biomarkers following neurotrauma assisted in improving outcome prediction and guiding therapy. The use of neuroproteins as diagnostic parameters requires a detailed knowledge of their dynamics in biological fluids for an appropriate interpretation. S100B is the most widely studied neuromarker, and its concentration in serum and cerebrospinal fluid (CSF) reflects the extent of brain damage. Neuron-specific enolase (NSE) is considered reflecting neuronal damage, while Beta-Trace is a lepto-meningeal protein used to diagnose CSF leakage. In five patients treated with an external ventricular drain (EVD) because of aneurysmal subarachnoid hemorrhage (SAH, n=3) or postinfectious hydrocephalus (n=2), an EVD exchange was performed 8 to 12 days after initial insertion. S100B and NSE were measured with the Cobas e411(®) electrochemiluminescence assay (Roche Diagnostics, Mannheim, Germany) and Beta-Trace with the BN Pro Spec(®) nephelometer (Dade Behring/Siemens, Germany) 1 h before EVD exchange, upon the insertion of the new drain, and 1, 3, 6, 12, 18, 24 and 48 h after EVD exchange. Before EVD exchange, S100B CSF concentrations were within the normal range in all patients (1.48 ± 0.37 μg/L), while NSE CSF concentrations were normal in four of five patients (6.51 ± 2.98 μg/L). Following EVD exchange, S100B and NSE CSF levels peaked significantly at 3 h after insertion of the new drain (S100B 39.02 ± 9.17 μg/L; NSE 54.80 ± 43.34 μg/L). S100B serum levels were slightly increased 6 to 24 h after EVD exchange. Beta-Trace concentrations in the CSF were not altered by EVD insertion. Our data demonstrate that EVD insertion results in a distinct increase of S100B and NSE concentrations in the CSF. Thus, the tampering of brain-derived protein concentrations in the CSF by diagnostic or therapeutic procedures has to be considered in the interpretation of neuromarker levels.