Objective To evaluate the efficacy and safety of presetting negative pressure drainage for anastomotic leakage after esophageal cancer surgery. Methods The clinical data of 68 patients with intrathoracic anastomotic leakage following surgery of esophageal and cardial carcinoma from January 2008 and January 2014 were retrospectively analyzed The patients were divided into 3 groups, including presetting negative pressure drainage group (Group A), endoscopy drainage placement group (Group B) and traditional treatment group (Group C ). Results A total of 1 251 patients underwent intrathoracic anastomosis were analyzed and anastomotic leakage occurred in 68 cases (5.4%), with 14(20.6%) died after operation. The mortality rates of Group A and Group B were significantly lower than that in Group C (14.3%, 0 vs 39.1%,P<0.05). The repeated drainage times in Group A and Group B were signficantly less than that in Group C (P<0.05). Compared with Group B and Group C, Group A had the advantage of shorter manipulation time (P<0.05). Drainage lavaging time, recovery time and retaining time of gastric tube in Group A and Group B were significantly shorter than those in Group C(P<0.05). Patients in Group A and Group C had significantly less discomfort in nasopharynx and significantly lower obstruction incidence compared with those in Group B (P<0.05). Except for death, all patients with anastomotic leakage had normal diet and safe discharge after prompt treatment. Conclusion Presetting negative pressure drainage after esophageal cancer surgery has a better effect for anastomotic leakage by reducing recovery time, lowering mortality rate and alleviating the suffering of patients.