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Introduction: Stenotrophomonas maltophilia has a high mortality risk, with rates estimated to be between 23-77%. Trimethoprim/sulfamethoxazole (TMP/SMX) or minocycline (MIN) are the mainstay treatment of S. maltophilia. However, there is a lack of comparative clinical data comparing the two antibiotics. The objective of this study was to assess clinical outcomes between patients treated with TMP/SMX or MIN for pneumonia due to S. maltophilia. Methods: This was a retrospective cohort study of patients admitted to an ICU at the Detroit Medical Center from August 20th, 2019 to February 19th, 2024. Adult patients with clinical signs of pneumonia; a culture growing S. maltophilia; and who received TMP/SMX or MIN ≥ 48 hours were included. Patients were excluded if they received combination therapy; had a non-susceptible S. maltophilia isolate; or died or were transferred to hospice within 48 hours of treatment. The primary outcome was 28-day all-cause mortality. Secondary outcomes included 28-day ventilator free days, ICU length of stay, in-hospital mortality, clinical response at EOT, and rates of adverse effects including hyperkalemia and hepatotoxicity. Results: A total of 71 patients were included (TMP/SMX, n=37; MIN, n=34). A majority of patients were male (62%) and African American (66%). Baseline characteristics were similar, though more patients in the MIN group had recent surgery (26.4% vs. 8.1%, p=0.01) and a higher Charlson Comorbidity Index (4.3 vs. 3.1, p=0.03); more patients in the TMP/SMX group had COPD (14.7% vs. 32.4%, p=0.04). Baseline SOFA scores (MIN=4.9 vs. TMP/SMX=5.7, p=0.15) were similar between the two groups. A majority of cultures were polymicrobial (82.5%). The primary outcome of 28-day all-cause mortality occurred in 29% of MIN patients and 32% of TMP/SMX patients (p=0.39). Mean 28-day ventilator free days (10.5 vs. 10.1, p=0.46), ICU length of stay (24 vs. 20, p=0.39), in-hospital mortality (41% vs. 40%, p=0.47), and clinical response at EOT (55% vs. 56%, p=0.47) were similar for TMP/SMX and MIN, respectively. Rates of adverse effects were similar between groups. Conclusions: TMP/SMX had similar rates of mortality and clinical outcomes when compared to MIN for the treatment of S. maltophilia. Future prospective trials should be conducted to confirm the results of this study.