Introduction: Orthopedic implant-associated infections caused by multidrug-resistant Enterobacteriaceae are a growing challenge for healthcare providers due to their increasing incidence and the difficulties of medical and surgical treatment. Material and Methods: A retrospective observational study of all cases of multidrug resistant Enterobacteriaceae orthopedic implant-associated infection diagnosed in a tertiary European hospital from December 2011 to November 2017 was carried out. Clinical records were reviewed using a previously designed protocol. Data analysis was performed with IBM® SPSS®, version 22. Results: 25 patients met inclusion criteria. The infected implants included 10 prosthetic joints, seven osteosyntheses, six combinations of prosthetic joint and osteosynthesis material, and two spacers. Of the multidrug resistant Enterobacteriaceae obtained on culture, 12 were extended-spectrum beta-lactamase-producing Escherichia coli, three OXA-48-producing Klebsiella pneumoniae, nine extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, and one extended-spectrum beta-lactamase-producing Proteus mirabilis. Combination antimicrobial therapy was employed in all cases but two. Overall, 16 (64%) patients underwent implant removal. The rate of infection control in the overall implant removal group was 100% compared to 33% in the implant retention group. A strong relationship between implant removal and infection control was observed (p = 0.001). Discussion: Implant removal is strongly associated with infection control. However, in some cases, patient age and comorbidity contraindicate hardware extraction. Potential objectives for future studies should be geared towards targeting the population in which debridement, antibiotic therapy, and implant retention can be used as a first-line therapeutic strategy with a reasonable probability of achieving infection control.