Objective To explore the clinical effect of failure mode and effect analysis (FMEA) combined with PDCA cycle management model in the prevention and control of multidrug-resistant organisms (MDROs) in intensive care unit (ICU), and provide evidences for drawing up improvement measures in healthcare-associated MDRO infections in ICU. Methods In January 2020, a risk assessment team was established in the Department of Critical Care Medicine, the First People’s Hospital of Longquanyi District of Chengdu, to analyze the possible risk points of MDRO infections in ICU from then on. FMEA was used to assess risks, and the failure modes with high risk priority numbers were selected to evaluate the high-risk points of MDRO infections. The causes of the high-risk points were analyzed, and improvement measures were formulated to control the risks through PDCA cycle management model. The incidence of healthcare-associated MDRO infections in ICU, improvement of high-risk events, and satisfaction of doctors and nurses after the implementation of intervention measures (from January 2020 to June 2021) were retrospectively collected and compared with those before the implementation of intervention measures (from January 2018 to December 2019). Results Six high-risk factors were screened out, namely single measures of isolation, unqualified cleaning and disinfection of bed units, irrational use of antimicrobial agents, weak consciousness of isolation among newcomers of ICU, weak awareness of pathogen inspection, and untimely disinfection. The incidence of healthcare-associated MDRO infections was 2.71% (49/1800) before intervention and 1.71% (31/1808) after intervention, and the difference between the two periods was statistically significant (χ2=4.224, P=0.040). The pathogen submission rate was 56.67% (1020/1800) before intervention and 61.23% (1107/1808) after intervention, and the difference between the two periods was statistically significant (χ2=7.755, P=0.005). The satisfaction rate of doctors and nurses was 75.0% (30/40) before intervention and 95.0% (38/40) after intervention, and the difference between the two periods was statistically significant (χ2=6.275, P=0.012). Conclusions FMEA can effectively find out the weak points in the prevention and treatment of MDRO infections in ICU, while PDCA model can effectively formulate improvement measures for the weak points and control the risks. The combined application of the two modes provides a scientific and effective guarantee for the rational prevention and treatment of MDRO infections in ICU patients.