Objective To analyze the occurrence and direct economic loss of post-operative healthcare-associated infection (HAI) in patients undergoing esophageal cancer surgery, and provide basis for the prevention and control of HAI. Methods A 1∶1 case-control study was used to retrospectively analyze patients undergoing esophageal cancer surgery in a hospital from January 2018 to December 2019, patients with post-operative HAI were in case group, those without post-operative infection were in control group, hospitalization time and medical expense of two groups of patients were compared. Results The median hospitalization time of case group and control group were 37.0 days and 16.0 days respectively, the increased hospitalization time due to HAI was 21.0 days, difference was statistically significant (P < 0.001). The median total hospitalization expense of case group and control group were 131 170.3 Yuan and 90 455.6 Yuan respectively, direct economic loss due to infection was 40 714.7 Yuan, diffe-rence was statistically significant (P < 0.001). Hospitalization days and expense in patients with multiple site infection were higher than those with single site infection, difference was statistically significant (both P < 0.05), patients with pulmonary infection and bloodstream infection had longer hospitalization days and higher hospitalization expense than control group. Conclusion Post-operative HAI in esophageal cancer patients can significantly prolong the length of hospital stay and increase the expense of hospitalization, the impact of different infection sites on the direct economic loss of patients is different, prevention and control of HAI in patients undergoing esophageal cancer surgery should be strengthened.