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Introduction: Patients receiving extracorporeal membrane oxygenation (ECMO) are at heightened risk for multidrug-resistant organism (MDRO) infections. However, antimicrobial resistance trends in ECMO patients compared to non-ECMO populations remain under-characterized. Methods: We conducted a retrospective cohort study of 81 ECMO patients (2019–2023) at a tertiary academic center. ECMO-specific antibiograms were constructed using all isolates obtained throughout the ECMO course, capturing evolving resistance patterns. Organism–antibiotic susceptibility data were compared with 2021 MICU and hospital-wide antibiograms. Only organisms with ≥20 isolates were included in comparative analyses. Fisher’s exact test was used to assess statistical significance (α = 0.05). AI-assisted tools were used for the statistical coding and editorial refinement. Results: The most common ECMO Gram-negative isolates were K. pneumoniae (18.7%), P. aeruginosa (17.2%), and K. aerogenes (10.3%). MDRO infections occurred in 38% (31/81) of ECMO patients. ECMO isolates demonstrated significantly lower susceptibilities for key agents: K. pneumoniae cefepime susceptibility was 75.7% (ECMO) vs. 85% (MICU) vs. 93% (hospital); p = 0.0152; P. aeruginosa piperacillin-tazobactam: 58.8% (ECMO) vs. 81% (MICU) vs. 90% (hospital); p = 0.0032; P. aeruginosa meropenem: 62.9% (ECMO) vs. 96% (MICU) vs. 90% (hospital); p = 0.0062; K. aerogenes ceftriaxone/aztreonam: 61.9% (ECMO) vs. >94% (hospital); p < 0.01. While aminoglycosides retained high susceptibility (e.g., 100% for amikacin), ECMO isolates of K. pneumoniae had lower susceptibility to tobramycin (78.4% vs. 91% MICU vs. 96% hospital). Conclusions: ECMO patients experience significantly higher rates of antimicrobial resistance compared to MICU and hospital-wide cohorts. Hospital antibiograms may underestimate resistance patterns in this population. ECMO-specific antibiograms should be adopted to guide empiric antimicrobial therapy and improve infection outcomes in critically ill patients.