Hyponatremia, a serum sodium level of <135 mEq/L, is the most common electrolyte abnormality occurring in 5%–35% of hospitalized patients. It is a predictor of increased morbidity and mortality. Diuretics, psychotropic, and antiepileptic drugs are commonly implicated in drug-induced hyponatremia. Trimethoprim-sulfamethoxazole and spironolactone are two commonly prescribed drugs; unfortunately, most providers are unfamiliar with these two drugs causing hyponatremia. Simultaneous use of trimethoprim-sulfamethoxazole and spironolactone can cause serious drug interactions that increase the risk of hyponatremia, hyperkalemia, and overall mortality. Despite recommendations to avoid using these two drugs concurrently, many healthcare providers continue to prescribe them together. We report a case of an elderly female with severe hyponatremia caused by trimethoprim-sulfamethoxazole superimposed on a chronic but stable mild hyponatremia.