In a randomized, prospective, controlled clinical study, methoxyflurane anesthesia produced high-output renal insufficiency. A syndrome was observed, characterized by polyuria, lack of responsiveness to infusion of vasopressin injection, marked weight loss, and delayed return to preoperative renal concentrating ability. Also noted were hypernatremia, serum hyperosmolality, elevated blood urea nitrogen levels, increases in serum creatinine and serum uric acid, and a decrease in uric acid clearance. These changes indicate a lesion of the distal nephron. Polyuria and dehydration following operation added difficulty to the clinical treatment of six of the 12 patients studied. All of the remaining six patients had abnormalities of at least one of the variables measured.