Different kinds of complications after splenectomy in hepatolenticular degeneration patients with hypersplenism have been reported in the past decades, but studies on pancreatic fistula and the corresponding targeted prevention and treatment after splenectomy still remain much unexplored. The present work investigated the pathogenic factors of pancreatic fistula after splenectomy and the variation tendency of amylase in drainage fluid, aiming to verify the significance of monitoring amylase in the abdominal drainage fluid in the early diagnosis of pancreatic fistula after splenectomy. One hundred sixty-seven patients with hepatolenticular degeneration and hypersplenism who underwent splenectomy in the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from January 2016 to August 2018 were selected and analyzed. The amylase in the abdominal drainage fluid was monitored routinely after splenectomy. We also conducted the statistics on the incidence of different types of pancreatic fistula and analyzed the influence factors of pancreatic fistula formation. After splenectomy, biochemical fistula occurred in 11 patients (6.6%), grade B fistula in six patients (3.6%), grade C fistula in one patient (0.6%), and the incidence of pancreatic fistula was 4.2 per cent (biochemical fistula excluded). The amylase in the peritoneal drainage fluid was closely concerned with the incidence of pancreatic fistula according to our statistics. Furthermore, by analyzing the different influence factors of pancreatic fistula, Child-Pugh grading of liver function (P = 0.041), pancreatic texture (P = 0.029), degree of splenomegaly (P = 0.003), and operative method (P = 0.001) were supposed to be closely related to the formation of pancreatic fistula. Monitoring of amylase in peritoneal drainage fluid is regarded as an important physiological parameter in the early diagnosis of pancreatic fistula after splenectomy, which provides effective clinical reference and plays a significant role in preventing the occurrence and development of pancreatic fistula.