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Introduction: Trimethoprim-sulfamethoxazole (TMP-SMX) use in immunocompromised patients can cause dose-dependent electrolyte irregularities including hyponatremia, hyperkalemia, and metabolic acidosis. We report a case of isolated hyponatremia caused by low-dose TMP-SMX use in an immunocompetent patient that mimicked the syndrome of inappropriate antidiuretic hormone secretion (SIADH)., Case Presentation: A 72-year-old woman was admitted to the hospital for acute onset of weakness and ambulatory dysfunction after starting TMP-SMX (160 mg/800 mg). She was found hyponatremic (sodium level, 125 mmol/L, down from 141 mmol/L prior to medication initiation). After ruling out diuretics use, and adrenal and thyroid dysfunction, we started her on intravenous saline infusion to manage her TMP-SMX-induced hyponatremia, and her symptoms resolved., Discussion: Electrolyte problems in immunocompromised patients treated for opportunistic infections with high-dose TMP-SMX (≥ 8 mg/kg/d TMP) are well-documented. However, the effects in immunocompetent patients are uncommon when standard dose (< 8 mg/kg/d TMP) is used., Conclusions: TMP-SMX blocks the aldosterone-mediated sodium reabsorption in the collecting ducts, and the trimethoprim component itself is structurally similar to potassium-sparing diuretics, which block sodium uptake at the distal nephron-both of which can cause hyponatremia., (Copyright© Board of Regents of the University of Wisconsin System and The Medical College of Wisconsin, Inc.)