Background and study aim: Reported complications of double-balloon enteroscopy (DBE) include post-enteroscopy pancreatitis. Hyperamylasemia after proximal DBE is reported frequently, but the relationship to development of pancreatitis remains unclear. Hyperamylasemia may be related to balloon inflation in the pancreatic head region. The aims of the study were to identify risk factors for hyperamylasemia and to determine the incidence of hyperamylasemia and pancreatitis when a modified cautious DBE insertion protocol was used. Patients and methods: In a prospective study, involving consecutive patients undergoing a proximal DBE, serum amylase activity was assessed immediately before and after the procedure. Results: 135 patients were included (men 78, women 57: mean age 49 years [range 17-88]). The mean total procedure time was 73 minutes (range 30-150 minutes), and mean number of passes during the proximal DBE was 14 (6-24). While patients (17%) developed hyperamylasemia after the DBE procedure, only one patient with hyperamylasemia had clinical symptoms indicating a mild acute pancreatitis (0.7%). Total procedure time and number of passes correlated significantly with the occurrence of hyperamylasemia. Conclusions: We found a low incidence of hyperamylasemia and pancreatitis post-DBE. Theoretically, this could result from the modified insertion technique, with local strain and friction of the small bowel as remaining causes of hyperamylasemia, a notion supported by the significant relation between hyperamylasemia and duration of DBE and total number of passes. We therefore advise use of the cautious insertion technique and, if possible, reduction of duration and of number of passes in every proximal DBE.