Objective To conduct healthcare -associated infection (HAI) risk assessment for each clinical department in the hospital, identify priority projects for infection risk control, and apply the integrated enterprise risk management framework (COSO-ERM) to build an optimized management system for extremely high risk departments. Methods According to the monitoring data from April to June 2021, risk identification, risk indicators establishment and weight coefficient assignment in 37 clinical departments in a hospital was carried out, and risk of HAI in the departments was assessed from three aspects (possibility of risk occurrence, severity of consequences, and current management system) in July 2021, percentile was adopted to conduct stratified risk assessment accor-ding to common departments and ICU departments, risk levels was determined, risk control measures for extremely high-risk departments and projects were taken, COSO-ERM optimization management system was built to evaluate the effect before and after risk assessment. Results General departments and ICU departments respectively rated one department with extremely high risk, namely neurosurgery and general ICU, COSO-ERM optimization management system of neurosurgery and general ICU were constructed respectively, intervention effect was evaluated. Compared with risk indicator value in April-June 2021, compliance rate and accuracy rate of hand hygiene in hand hygiene indicator improved, utilization rate of devices reduced, incidence of VAP in inpatients reduced in April-June 2022, differences were all significant (all P < 0.05). Conclusion Neurosurgery and general ICU are departments with extremely high risk of HAI, which should give priority to risk control, building a risk optimization ma-nagement system is conducive to infection risk control.