Pentostatin is an adenosine deaminase inhibitor used in the treatment of hairy cell leukemia and T-cell lymphomas. A 27-year-old man with refractory cutaneous T-cell lymphoma developed severe hyponatremia 3 days after completing his first cycle of pentostatin therapy. Shortly after hospital admission, he became disoriented and was admitted to the medical intensive care unit and treated with a combination of hypertonic saline, intravenous diuretics, and fluid restriction to reestablish normal sodium homeostasis. The mechanism by which pentostatin may have induced hyponatremia in this patient is unknown; clinical and laboratory findings represented both extrarenal sodium loss and syndrome of inappropriate antidiuretic hormone. Clinicians should be aware of the possible development of life-threatening symptomatic hyponatremia in patients receiving pentostatin.