Abstract: OBJECTIVE To explore the direct economic burden of diseases caused by four types of healthcare-associated infections (HAI), and to provide an economic basis for infection prevention and control. METHODS A retrospective survey was conducted on 395 798 inpatients admitted to Huaibei People's Hospital from 2016 to 2023. Patients were divided into case and control groups based on whether they developed surgical site infection (SSI), ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (CAUTI) or central line-associated bloodstream infection (CLABSI). A 1∶1 matched case-control study method was employed to compare and analyze the direct economic burden caused by SSI, VAP, CAUTI and CLABSI. RESULTS A total of 266 pairs of cases were successfully matched, including 111 pairs of SSI, 77 pairs of VAP, 51 pairs of CAUTI and 27 pairs of CLABSI. The extended hospital stays due to SSI, VAP, CAUTI and CLABSI were 17.00, 13.00, 8.00 and 14.00 days, respectively (P<0.05). The increased hospitalization costs were 11 886.91, 46 172.27, 7 151.42 and 13 237.08 yuan, respectively (P<0.05). Among them, the hospital stays for SSI due to internal fixation replacement and VAP caused by multidrug-resistant bacteria increased the most (by 20.00 and 17.50 days, respectively), and the cost increase for VAP caused by multidrug-resistant bacteria was the most significant (by 51 118.75 yuan). The SSI due to hernia and CLABSI resulted in the largest increase in hospitalization costs (2.39 times). CONCLUSIONS The occurrence of SSI, VAP, CAUTI and CLABSI in inpatients significantly increases the length of hospital stay and hospitalization costs. These infections should be prioritized in infection prevention and control efforts, and continuous improvement strategies should be implemented to manage them. This is of great significance for promoting steady improvement in medical quality and safety, as well as increasing the economic and social benefits of hospitals.