Background: Tramadol poisoning is one of the major health problems worldwide especially in developing countries. Seizure is considered a serious and life-threatening manifestation of acute tramadol overdose. Recently, serum S100B protein has been shown to be a useful and specific neuro-biochemical marker of central nervous system damage. Aim of the study: To assess the role of serum S100B protein on admission as a predictor of seizure occurrence in patients with acute tramadol poisoning and to determine the factors affecting tramadol-induced seizure. Participants and methods: Thirty-three patients with acute tramadol poisoning, of both sexes, and 20 healthy sexand age-matched volunteers as a control group were included in this study. The studied tramadol poisoned patients were classified into two groups; group I: Seizure group and group II: Non-seizure group. For all patients, demographic and poisoning data were recorded then clinical evaluation and investigations were performed. Serum S100B level was estimated on admission. Results: : There was a statistically significant difference between patients with seizures and patients without seizures regarding age group, gender, ingested tramadol dose, Glasgow coma scale (GCS), poisoning severity score (PSS) and administered naloxone dose. On the other hand, there was no significant difference between both groups in manner of poisoning, delay time, vital data, oxygen saturation, arterial blood gases & pH and hospitalization period. The mean serum S100B was significantly higher in tramadol poisoned patients when compared to the control group; moreover, it was significantly elevated in patients with seizures than patients without seizures. Serum S100B as a predictor of seizures showed AUC =0.863 (p=<0.001) at cut-off value >0.58 µg/L with 75 % sensitivity and 95.24 % specificity. Conclusion: Serum S100B could be used as a good predictor of tramadol-induced seizure and it could be useful to assess clinical severity in acute tramadol overdose. Moreover, young adult males, increased ingested tramadol dose, increased administered naloxone dose and decreased level of consciousness are considered risk factors of tramadol-induced seizures.