Objectives: The method for drainage of exocrine secretions in pancreas transplantation remains a matter of debate. Different methods have evolved over time. Most data on these methods are from single-center studies with small sample sizes. Larger studies have yielded conflicting results. Methods: Data from the United Network for Organ Sharing database on all adult subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 19,934). Subjects were divided into 3 groups: enteric drainage with Roux-en-Y (n = 4308), enteric drainage without Roux-en-Y (n = 11,145), and bladder drainage (n = 4481). Primary end points were patient and graft survival at 1, 3, 5, 10, and 15 years. Results: There was a patient and graft survival advantage with enteric drainage without Roux-en-Y reconstruction compared with the other methods. This was consistent at 1, 3, 5, 10, and 15 years. Conclusions: Our study demonstrated increased graft and patient survival when comparing enteric drainage of the transplanted pancreas without Roux-en-Y reconstruction to enteric drainage with Roux-en-Y and bladder drainage at 1, 3, 5, 10, and 15 years. Based on this study, we recommend enteric drainage without Roux-en-Y reconstruction as the method of choice in pancreas transplantation.