BACKGROUND Refractory hypokalemia has been rarely demonstrated in patients with acute monocytic leukemia (AMoL). Hypokalemia develops in these patients owing to renal tubular dysfunction, secondary to lysozyme enzymes that are released by monocytes in AMoL. Additionally, renin-like substances are produced from monocytes and can lead to hypokalemia and metabolic alkalosis. There is also an entity called spurious hypokalemia, in which high numbers of metabolically active cells in blood samples increase sodium-potassium ATPase activity, resulting in influx of potassium. Additional research is warranted regarding this specific demographic to create standardized treatment approaches to electrolyte repletion. CASE REPORT In this case report, we demonstrate a rare case of an 82-year-old woman with AMoL, complicated by refractory hypokalemia, who presented with concerns of fatigue. The patient's initial laboratory results were significant for leukocytosis with monocytosis and severe hypokalemia. Refractory hypokalemia was noted, despite administration of aggressive repletions. During her hospitalization, AMoL was diagnosed and an extensive workup was performed to evaluate the underlying cause of hypokalemia. Ultimately, the patient died on day 4 of hospitalization. We describe the correlation between severe refractory hypokalemia and leukocytosis and provide a literature review of multiple etiologies of refractory hypokalemia in patients with AMoL. CONCLUSIONS We evaluated the numerous pathophysiologic mechanisms responsible for refractory hypokalemia in patients with AMoL. Our therapeutic outcomes were limited owing to the patient's early death. It is of high importance to evaluate the underlying cause of hypokalemia in these patients and to treat accordingly with caution.