Objective To establish a comprehensive and scientific risk assessment system under the normalized si-tuation of coronavirus disease 2019 (COVID -19) prevention and control, and provide support for decision-making of hospital management. Methods A comprehensive tertiary first-class hospital in Shandong Province was as the research object, risk assessment was carried out on hospital at overall level, risk points and risk indicators were determined with brainstorming method by members of healthcare-associated infection (HAI) management committee, risk scores of clinical departments were calculated through risk assessment matrix, risk grades were assessed with percentile method, differences among different risk groups were compared using one-way ANOVA or non-parame-tric test, clinical departments were performed stratified clustering analysis according to the difference of risk scores of risk points, the evaluated extremely high-risk departments were conduct internal risk assessment with failure model and effect analysis, and risk response was finally carried out according to results of two rounds of risk assessment. Results A total of 61 clinical departments participated in the assessment. Eight risk points and 24 risk indicators were ultimately determined by the risk assessment of the clinical departments. Risk grades assessment results indicated that the extremely high-risk departments were respectively as follows: neurosurgical departmentⅠ, neurosurgical departmentⅡ, neurological intensive care unit, respiratory intensive care unit and intensive care units, accounting for 8.20%; risk scores of management indicators, process indicators and outcome indicators of six risk groups were all significantly different (all P < 0.05); clinical departments were divided into 3 categories accor-ding to their characteristics with stratified cluster analysis, which were designated as general departments clustering group, key departments clustering group and neurosurgery department clustering group. Seven high-risk priority issues were assessed through internal risk assessment of extremely high-risk departments, targeted solutions were put forward. Conclusion The risk assessment system established in this study can effectively assess and analyze the risk grade of clinical departments, effectively respond to the high-risk priority issues of extremely high-risk departments, and clarify the key points of HAI management in the next step.