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Hydrochlorothiazide has been shown to cause rare, but serious non-cardiogenic pulmonary edema. We present a case report of a patient with apparent septic shock and acute respiratory distress syndrome (ARDS) requiring life-sustaining veno-venous extracorporeal membrane oxygenation (VV-ECMO). Upon further review of the literature and the chronology of the patient’s presentation, her condition was most likely due to an immune-mediated reaction to hydrochlorothiazide. This represents the first case, to our knowledge, of such a severe reaction to hydrochlorothiazide supported with ECMO therapy.