Recovery of liver cell mass following hepatectomy requires a metabolic compromise between differentiated function and organ regrowth. Clinical experience has shown that hepatic failure after resection is more common when the organ is diseased. We have evaluated intracellular hepatic biochemistry in patients with normal and cirrhotic livers undergoing partial hepatectomy, using 31-phosphorus magnetic resonance spectroscopy (31P MRS). Eighteen patients were studied, half with normal liver architecture (normal group, n = 9) and half with cirrhotic parenchyma (cirrhosis group, n = 9). Magnetic resonance examinations were performed preoperatively and on postoperative days 2, 4, 6, 14, and 28. Hepatic volume (estimated by magnetic resonance imaging [MRI]) and blood chemistries were measured at the same intervals. Following a comparable reduction in parenchymal volume, the cirrhotic group demonstrated a more sustained fall in adenosine triphosphate (ATP) energy state. Disturbance of membrane phospholipid metabolism and duration of acute-phase reaction were more marked when the liver was diseased. The pattern of derangement of hepatic function, however, was similar in the two groups. Overall, the recovery process was less efficient in the cirrhotic organ, and culminated in a diminished rate and extent of the regenerative response. These outcomes indicate that liver regeneration after partial hepatectomy involves modulation of hepatic energy economy in response to changing work demands. The efficiency of this process is influenced by the histopathologic state of the organ, and in turn governs the physiologic reserve. These findings may explain the mechanism of posthepatectomy liver failure, and offer a rational basis for the assessment of novel hepatic support strategies. (HEPATOLOGY 2001;34:557-565.)