Background: The neuroprotein S100 released into the circulation has been suggested as a reliable marker for primary brain damage. However, safe identification of relevant traumatic brain injury (TBI) may possibly be hampered by S100 release from peripheral tissue. The objective of this study was to measure early S100 levels using the Elecsys((R)) S100 immunoassay for real-time assessment of severe TBI in multiple trauma. Methods: Consecutively admitted multiple trauma patients (injury severity score >= 16 points) were stratified according to the results of the initial cerebral computed tomography (CCT) examination. S100 serum levels were determined at admission and at 6, 12, 24, 48 and 72 h after trauma. Data were correlated to creatine phosphokinase (CK) and lactate dehydrogenase (LDH) serum levels. Using receiver operating characteristic (ROC) analysis, the discriminating power of S100 measurement was calculated for the detection of CCT+ findings. Results: Median S100 levels of CCT+ patients (n=9; 37 years) decreased from 3.30 mu g/L at admission to 0.41 mu g/L 72 h after trauma. They revealed no significant differences to CCT- patients (n=18; 44 years), but remained elevated compared to controls. Median CK and LDH levels correlated with the corresponding S100 levels during the first 24 h after trauma. ROC analysis displayed a maximum area under the curve of only 0.653 at 12 h after trauma. No significant difference was calculated for the differentiation between CCT+ and CCT- patients. Conclusions: Measurements of S100 serum levels using the Elecsys((R)) S100 immunoassay are not reliable for the real-time detection of severe TBI in multiple trauma patients. Due to soft tissue trauma or bone fractures, S100 is mainly released from peripheral sources such as adipocytes or skeletal muscle cells.