A small proportion of patients with mild head injury (MHI) develop post-concussion symptoms (PCSs). We searched simple measures for the early detection of patients who are probable to develop PCSs. We recorded signs and symptoms, history of previous diseases, medications, and lifestyle factors and measured serum protein S-100B on admission in a series of 172 consecutive MHI patients admitted into the emergency room of a general hospital. A modified Rivermead Post-Concussion Symptoms Questionnaire was used to identify the patients with and without PCSs 1 month after the injury. We identified 37 patients with MHI who developed PCSs (22%). Odds ratios (OR) and 95% confidence intervals (CI) after adjustment for possible confounding variables were calculated by logistic regression. Independent early risk factors for PCSs in the MHI patients were skull fracture (OR 8.0, 95% CI 2.6–24.6), serum protein S-100B ≥ 0.50 μg/l (OR 5.5, 95% CI 1.6–18.6), dizziness (OR 3.1, 95% CI 1.2–8.0), and headache (OR 2.6, 95% CI 1.0–6.5). Serum protein S-100B proved to be a specific, but not sensitive predictor of PCSs. The presence of skull fracture, elevated serum protein S-100B, dizziness, and headache may help the emergency room physician to identify patients at risk of PCSs and to refer them for further examination and follow-up.