Tramadol is a centrally acting synthetic analgesic. Recently, tramadol overdose has become one of the most common causes of acute poisoning in Egypt and worldwide. Common symptoms of toxicity include respiratory depression and seizure. Hypoglycemia is another potentially fatal hazard that is newly emerging in association with tramadol. Therefore, the aim of this study is to investigate the effect of tramadol poisoning on blood glucose level and whether or not this effect is associated with tramadol-induced acute pancreatitis. Methods: A prospective study was conducted on patients admitted to the Poison Control Center, Ain Shams University hospitals from November 2014 to August 2016 with acute tramadol poisoning. All the patients were subjected to complete medical history, physical examination and routine biochemical laboratory tests. In addition to, measurement of serum levels of amylase, lipase and insulin. Blood glucose level was obtained twice; on admission and on the second day. Results: twenty nine patients, 25 males (86.2%) and 4 females (13.79%) met inclusion criteria. Mean age was (31.34 ± 8.75 years). There was significant decrease of blood pressure and respiratory rate in the tramadol poisoned patients (case group) as compared with the control group. The most frequent manifestations were; nausea and vomiting (93.1%), abdominal pain (86.2%), coma II (55.17%), miosis (37.93%) and sweating (34.48%). There was significant decrease of pH, PO2 and HCO3 and a significant increase of PCO2 in tramadol intoxicated patients. The case group showed significant decrease of glucose level on the second day as compared to the control group, as well as, when compared with glucose level on admission day. There was a significant increase of serum amylase level and a non-significant change of serum lipase and insulin levels among the case group in comparison with the control group. Conclusion: Fluctuations in blood glucose level particularly hypoglycemia can be considered a risk of tramadol poisoning. Acute tramadol toxicity seems unlikely to cause acute pancreatitis, despite the high amylase level. This debate still requires further studies. Clinicians should remain alert for serial blood glucose monitoring in tramadol poisoning.