Objective To investigate the incidence of healthcare-associated infection (HAI) in patients undergoing radical pancreatoduodenectomy (RPD), assess the economic burden caused by HAIs in these patients, and provide health and economic support for infection prevention and control. Methods Clinical data of patients who underwent RPD in a general surgery ward of a tertiary teaching hospital in Shandong Province from January 2020 to December 2022 were collected retrospectively. The incidences of HAIs in these patients were investigated. Patients were divided into the infection group and the non-infection group based on whether they developed postoperative HAI. A 1 ∶1 propensity score matching method was adopted to construct a covariate balanced database. The hospitalization expenses and length of hospital stay were compared between the two groups of patients, and the economic burden caused by HAIs was calculated. Results A total of 287 patients undergoing RPD were included in the analysis, of whom 35 developed HAI, with a HAI incidence of 12.20%. Propensity score matching method successfully matched 33 pairs. After matching, the median total hospitalization expenses for patients in the infection and non-infection groups were 120 722.0 Yuan and 100 367.0 Yuan, respectively, with the infection group incurring an additional total hospitalization expenses of 20 355.0 Yuan (P<0.05); the median length of hospital stay were 28 and 19 days, respectively, and the infection group had an extended length of hospital stay of 9 days (P<0.05). The analysis of individual costs for the two groups showed that, except for the expenses of surgical costs and hygiene mate-rials costs, all other medical expenditures were significantly higher in the infection group than in the non-infection group (all P<0.05). The economic burden caused by Western medicine costs was the highest, reaching 11 427.0 Yuan, followed by treatment costs (3 228.0 Yuan) and examination costs (2 304.0 Yuan). Except for the expenses of surgery and hygiene material costs, the constituent ratio of all other costs increased in the infection group, with the largest increase being in Western medicine costs, which rose by 2.66 %. Conclusion HAIs in patients under-going RPD can increase hospitalization expenses and prolong length of hospital stay. Prevention of postoperative HAIs is beneficial for reducing the economic burden on patients and hospitals.