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Objectives: Colistin is frequently used as a last-line treatment option for periprosthetic joint infections (PJIs) caused by multidrug-resistant (MDR) Gram-negative pathogens, and mortality rates are high in this patient group. This study aimed to evaluate 90-day mortality and its associated clinical factors in MDR Gram-negative PJI cases treated with colistin, with particular attention to the American Society of Anesthesiologists (ASA) score and changes in renal function during therapy. Methods: Patients diagnosed with MDR Gram-negative PJI and treated with intravenous colistin at a single center between 2010 and 2024 were retrospectively reviewed. Demographic data, infection localization, comorbidities, American Society of Anesthesiologists (ASA) score, causative pathogens, presence of sepsis, intensive care unit (ICU) admission, duration of colistin therapy, pre- and post-treatment renal function parameters, and mortality were all recorded. Survivors and non-survivors were compared using univariate analysis. Results: The cohort included 44 patients with a mean age of 72 years (23 women and 21 men). Infections involved the hip in 33 patients (75.0%) and the knee in 11 (25.0%). Twenty-two patients (50.0%) were in the high-ASA group (ASA ≥ III group). Within 90 days of initiating colistin therapy, 25 patients died and 19 survived. A high ASA score was significantly more common among non-survivors than among survivors (18/25 (72.0%) vs. 4/19 (21.1%); p < 0.001), and dialysis requirement was also more common among non-survivors [20/25 (80.0%) vs. 8/19 (42.1%); p = 0.013]. End-of-treatment renal parameters were significantly worse among non-survivors, including urea [71.2 (50.9–78.8) vs. 38.5 (34.8–42.5) mg/dL; p = 0.003], creatinine [2.29 (1.75–2.64) vs. 0.93 (0.72–1.60) mg/dL; p = 0.003], urea delta [42.8 (38.0–48.6) vs. −5.4 (−7.9 to −2.0) mg/dL; p = 0.006], and creatinine delta [0.78 (0.33–1.57) vs. 0.16 (0.10–0.57) mg/dL; p = 0.008] levels. In contrast, age, sepsis, ICU admission, and colistin treatment duration were not significantly associated with 90-day survival. Conclusions: In this high-risk cohort of patients with MDR Gram-negative PJI treated with colistin, the 90-day mortality rate was high and was associated with higher American Society of Anesthesiologists scores, dialysis requirements, and worsening renal function during treatment. No significant association was observed between treatment duration and response in this cohort. These findings should be interpreted cautiously, given the retrospective design and the limited sample size.