Infection with multi-drug resistant organisms (MDROs) has emerged as a global problem in medical institutions. Overuse of antibiotics is the main cause of drug resistance. Notably, the incidence of infection with MDROs increases in patients with limb fractures who have undergone invasive surgery. The present study aimed to analyze the risk factors for postoperative MDROs infection in a cohort of patients with limb fractures. A retrospective study was performed on the data of patients with fractures between January 2020 and August 2022. Postoperative surgical site infection occurred in 114 patients in total, of which 47 were infected with MDROs. Univariate logistic regression analysis and multivariate binary logistic regression were used to confirm the associations between independent risk factors and MDRO infection. A total of 155 bacteria were collected from patients with MDROs infection and patients with non-MDROs infection, of which 66.5% were gram-positive bacteria and 33.5% were gram-negative. Staphylococcus aureus accounted for 26.5% of the 155 pathogens. MDROs, such as methicillin-resistant S. aureus and extended-spectrum β-lactamases-positive gram-negative bacillus, were detected after antibiotic treatment. Univariate analysis indicated that the number of antibiotics administered, being bedridden, repeat infection, operative time and repeated operation were different in the two groups. In addition, univariate logistic analysis indicated that being bedridden (OR, 3.98; P=0.001), administration of >2 antibiotics (OR, 2.42; P=0.026), an operative time of >3 h (OR, 3.37; P=0.003), repeated infection (OR, 3.08; P=0.009) and repetition of procedures (OR, 2.25; P=0.039) were individual risk factors for MDRO infection. Multivariate analysis showed that being bedridden (OR, 2.66; P=0.037), repeated infection (OR, 4.00; P=0.005) and an operative time of >3 h (OR, 2.28; P=0.023) were risk factors of MDRO infection. In conclusion, constrained antibiotic use, shortened operative time and increased activity duration can effectively prevent surgical-site infection with MDROs in patients with fractures.