Background: Endoscopic biliary sphincterotomy in sphincter of Oddi dysfunction (SOD) patients has a high risk of post-ERCP pancreatitis. It is hypothesized that this high complication rate is due to residual pancreatic sphincter hypertension. Aim: To decrease the pancreatitis rate of SOD patients after biliary sphincterotomy by injecting botulinum toxin into the residual pancreatic sphincter. This is technically simpler and involves less pancreatic manipulation than pancreatic stent placement. Methods: All patients undergoing ERCP with manometry for suspicion of biliary SOD where asked to participate in this study. Manometry was performed to obtain baseline biliary and pancreatic sphincter pressures with at least two pull-through recordings. Patients with normal basal pressures (less than 40 mmHg) were excluded. Those with elevated pressures were randomized to receive botulinum toxin vs. sham saline injection after the biliary sphincterotomy. Fifty units of botulinum toxin was delivered via sclerotherapy needle as two 25 U injections of 0.25cc each into the pancreatic sphincter in the botulinum toxin therapy group. For those in the sham arm, 0.50cc of saline was injected into the duodenal lumen via sclerotherapy needle. All patients were assessed 24 hours post-procedure for complications. Results: Between 2/12/99 and 11/30/99 a total of 57 patients were referred for ERCP with manometry for suspected SOD. Fifty-one consented to participate in the protocol. Thirteen had elevated baseline pressures and were randomized. Six received botulinum toxin injection and 7 were randomized to sham injection. A total of 4 (57%) patients in the sham group developed procedure-induced pancreatitis as compared to 2 (33%) in the botulinum toxin group (NS). No differences were observed in the severity of pancreatitis between the groups. Conclusions: In the small number of patients studied to date, no definite conclusion can be made about the effect of botulinum toxin injection on the pancreatitis rate of SOD patients following biliary sphincterotomy.