Changes in hepatic ureagenesis following major hepatectomy are not well characterized. We studied the relation between urea synthesis and liver mass before and after major hepatectomy in humans. Fifteen patients scheduled for resection of malignancies in otherwise healthy livers were studied. Pre- and postoperative liver volume was assessed by computerized tomography-volumetry. During surgery, a primed, continuous infusion of [¹³C]urea was administered intravenously, and arterial blood samples were obtained hourly. Indocyanine green clearance was determined before and after resection. Seven patients underwent major hepatectomy, and eight patients underwent minor [<5% functional liver volume (total volume − tumor volume)] or no resection, serving as controls. Resected functional liver volume in the major hepatectomy group averaged 60%. Urea synthesis per gram of functional liver tissue increased 2.6-fold following major hepatectomy, maintaining whole body urea synthesis. Arterial ammonia remained unchanged throughout the study, whereas following hepatectomy a hyperaminoacidemia occurred. In conclusion, immediately following major hepatectomy, urea synthesis per gram of functional liver tissue increases rapidly and proportionately to the amount of liver tissue resected, maintaining whole body urea synthesis at preoperative levels. This rapid and complete adaptation suggests that the capacity of urea synthesis is not limiting the maximum resectable volume in otherwise healthy livers.