Background: Postoperative pancreatic fistula (PF) is still regarded as a major complication in pancreatic surgery. In the present study, we evaluated the risk of PF in a large study population of patients with neuroendocrine pancreatic tumors (NPT), pancreatic cancer (PC), and chronic pancreatitis (CP). Methods: Patients who underwent pancreatic surgery between 1989 and 2008 at our institution were retrospectively evaluated. Patients were analyzed regarding age, gender, BMI, alcohol, smoking, preoperative diabetes, reason for operation, operative procedure, and PF. Three different grades of PF (grades A, B, C) were defined. Results: 133 patients with NPT, 212 patients with PC, 52 patients with CP, and 76 patients with other reasons were evaluated. Patients with a NPT had a significant higher risk of developing a PF than patients with PC, CP, or other reasons (p = 0.0001). Enucleation of the tumor was associated with the highest rate of PF (p = 0.001). In a multivariate analysis, BMI >26, and preoperative diabetes were associated with a higher rate of PF (p = 0.042 and p = 0.02, respectively). Conclusion: We demonstrated that after excluding factors like different definitions of PF, or different peri- or postoperative management, patients with NPT have a significantly higher risk of postoperative PF than patients with other pancreatic diseases.