Cotrimoxazole (trimethoprim-sulfamethoxazole) is a combination antimicrobial that is frequently used to treat a wide variety of infections. Only recently has hyperkalaemia been recognised as a relatively common complication of therapy with trimethoprim. Hyperkalaemia has been demonstrated to occur with the administration of both high and standard dosages of trimethoprim. The recognition of this disorder of potassium homeostasis prompted the investigation and ultimate description of the mechanism by which trimethoprim causes hyperkalaemia. Trimethoprim was found to reduce renal potassium excretion through the competitive inhibition of epithelial sodium channels in the distal nephron, in a manner identical to the potassium-sparing diuretic amiloride. Increased risk for hyperkalaemia with trimethoprim treatment appears to be related to both higher dosages and underlying renal impairment. It is probable that other disturbances in potassium homeostasis, such as hyopoaldosteronism and treatment with medications that impair renal potassium excretion, are also risk factors for hyperkalaemia with trimethoprim therapy. Prevention of this adverse reaction depends upon recognition of patients at risk of developing hyperkalaemia as well as proper dosage selection of trimethoprim for the patient's prevailing glomerular filtration rate. Management of hyperkalaemia often mandates discontinuation of the drug, volume repletion with isotonic fluids, and other therapies specific to hyperkalaemia. In circumstances where continued treatment with trimethoprim is required, induction of high urinary flow rates with intravenous fluids and a loop diuretic, as well as alkalinisation of the urine, have been shown to block the antikaliuretic effect of trimethoprim on distal nephron cells.