Objective Healthcare-associated infection (HAI) outbreak events pose significant threat to healthcare system. This paper aims to provide a new perspective to explain the causal pathways of HAI outbreak events and seek effective prevention and control strategies. Methods Cases of HAI outbreak events were collected by literature review. Interaction among risk factors was explored through crisp-set qualitative comparative analysis (csQCA). Results Inadequate procedures such as disinfection, isolation, hand hygiene, and management system, as well as improper use of antimicrobial agents, invasive procedures, and low immune function of patients were the antece-dents of HAI outbreak events. Configuration analysis reveals that there were four pathways between HAI outbreak events and risk factors, and could be classified into two types: the isolation-management synergistic type and multi-factor co-promotion type. Conclusion Prevention and control of HAI outbreak requires coordinated effect of personnel isolation (including isolation of patients and protection of healthcare workers) and management, proper disinfection and isolation, and rational use of antimicrobial agents, so as to prevent infection outbreaks caused by the combination of risk factors.