BACKGROUND: Patients with infection by multi-drug-resistant organisms (MDROs) are often complicated, difficult to cure, require advanced antimicrobial drugs for treatment, and are susceptible to bacterial colonization. This places a heavy economic burden on patients, which can even lead to death, and also increases the economic burden on healthcare services. AIM: We aimed to systematically assess the risk factors for infection by MDROs in patients in the intensive care unit (ICU). METHODS: PubMed, Embase, MEDLINE, and the Cochrane Library were queried from database inception to 21 FINDINGS: This meta-analysis included 29 articles involving 18,063 patients, of whom 2955 had contracted MDRO infections. The results of the meta-analysis revealed that diabetes mellitus, cardiovascular disease, history of hospitalization within the previous year, abnormal liver function, history of MDRO infection, injury severity score, length of ICU stay, nasogastric tube, parenteral nutrition, colonization pressure, multiple traumas, mechanical ventilation, tracheostomy, central venous catheter, previous antibiotic treatment, immunosuppressive agents, piperacillin-tazobactam, multi-antibiotic treatment, glycopeptide antibiotics, carbapenems, imipenem, and nitroimidazoles were risk factors for MDRO infection in patients in the ICU. CONCLUSIONS: The ICU is a high-risk area for MDRO infection. Healthcare professionals should adopt prevention and control measures based on these risk factors to reduce the occurrence of MDRO infections.