PurposeNosocomial infection is a major threat to the health care system and patient welfare. After the pandemic, new protocols were established in hospitals and communities to protect against the transmission of COVID-19, which may have changed the incidence of nosocomial transmission. This study was conducted to compare the incidence of nosocomial infection before and after the COVID-19 pandemic. MethodsThis was a retrospective cohort study performed on trauma patients who were admitted, from May 22, 2018 to November 22, 2021, to the largest level-1 trauma center in Shiraz, Iran (Shahid Rajaei Trauma Hospital). All the trauma patients over 15 years old admitted during the study time were included in this study. Individuals who were declared dead upon arrival were excluded. Patients were evaluated in 2 periods: before the pandemic (May 22, 2018 – February 19, 2020) and after the pandemic (February 19, 2020 – November 22, 2021). Patients were assessed based on demographic information (age, gender, length of hospital stay, and patient outcome), the occurrence of hospital infection, and the type of infection. The analysis was done using SPSS version 25. ResultsOverall, 60,561 patients were admitted, with a mean age of 40 years. Nosocomial infection was diagnosed in 4.00% (n = 2423) of all admitted patients. The incidence rate of post-COVID-19 hospital-acquired infections decreased by 16.28% (p < 0.001) when compared to before the pandemic; in contrast, surgical site infection (p < 0.001) and urinary tract infection (p = 0.043) were responsible for this change, while hospital-acquired pneumonia (p = 0.568) and bloodstream infection (p = 0.156) were not significantly different. Overall mortality was 1.79%, while 28.52% of all patients with nosocomial infections died. During the pandemic, there was a 25.78% increase (p < 0.001) in the overall incidence rate of mortality, which was also observed among patients with nosocomial infections (17.84%). ConclusionThe incidence of nosocomial infection has decreased during the pandemic, possibly due to the use of more personal protective equipment and modified protocols after the outbreak. This also explains the difference in the change in incidence rates of nosocomial infection subtypes.