Abstract High-dose trimethoprim-sulfamethaxazole is the drug of choice for treatment of severe Pneumocystis jiroveci pneumonia (PJP) with the caveat that at higher doses, serious adverse events occur more frequently. A lethal complication is hyperkalemia which often mandates premature discontinuation of therapy despite lower efficacy of second-line agents. We report a case of a patient with severe PJP causing respiratory failure treated with high-dose trimethoprim-sulfamethaxazole who experienced hyperkalemia, which was successfully managed with a combination of fludrocortisone and furosemide allowing completion of antibiotic course. Administration of fludrocortisone and furosemide may enable practitioners to effectively address trimethoprim-induced hyperkalemia in critically ill patients with PJP. We speculate that exogenous administration of fludrocortisone may promote transcription of ENaC-amiloride sensitive epithelial sodium channels, which is unaffected by circulating trimethoprim allowing for kaliuresis to be restored. The addition of furosemide increases sodium load, further promoting potassium excretion.