Purpose: This study of patients with minor head injury was designed to investigate the relation of S-100 protein measurements to computed tomography (CT) findings and patients outcomes. Increased serum levels of this protein were hypothetized to predict intracranial pathology and increased frequency of post-concussion symptoms. Methods: One hundred and eighty-two patients were studied with Glasgow Coma Scale scores of 13-15. The study recruited patients from three Scandinavian neurotrauma centres. Serum levels of S-100 protein were measured at admittance and CT scans of the brain were obtained within 24 hours post-injury in all patients. Outcome was evaluated with the Rivermead Postconcussion Symptoms Questionnaire (RPQ) 3 months after the injury. Results: Increased serum level of S-100 protein was detected in 69 (38%) patients, and CT scan demonstrated intracranial pathology in 10 (5%) (brain contusion in seven, epidural haematoma in two, traumatic subarachnoid haemorrhage in one). The proportion of patients with detectable serum level was significantly (p < 0.01) higher among those with intracranial pathology (90%) compared to those without (35%). The negative predictive value of an undetectable S-100 level was 0.99. Sixty-two per cent reported one or more post-concussion symptoms at follow-up. A trend was observed towards an increased frequency of post-concussion symptoms among patients with detectable serum levels. Conclusions: Undetectable serum level of S-100 protein predicts normal intracranial findings on CT scan. Determination of S-100 protein in serum may be used to select patients for CT scanning. Increased S-100 serum levels may be more related to post-concussion symptoms caused by mild traumatic brain injury than to symptoms of psychological origin.