Trimethoprim-sulfamethoxazole is a commonly prescribed antimicrobial agent. Twenty-five years after its introduction into clinical practice, an unrecognized and potentially lethal adverse reaction associated with trimethoprim-sulfamethoxazole therapy, hyperkalemia, was described. Both "high-dose" and "standard-dose" trimethoprim-sulfamethoxazole have been associated with this electrolyte disorder. Recognition of this potassium disturbance led to the subsequent description of the mechanism by which trimethoprim-sulfamethoxazole induced hyperkalemia. Trimethoprim was found to act like the potassium-sparing diuretic amiloride and reduce renal potassium excretion. Hence, trimethoprim is in fact a potassium-sparing diuretic like amiloride and causes hyperkalemia in high-risk patients.