Pancreatoduodenectomy with major hepatectomy has recently been employed for patients with advanced biliary malignancies as potential curative surgery. However, postoperative liver decompensation is a major unfavorable complication with this procedure; the main cause of the sequelae is disturbance growth. In our present study, hepatic regeneration and nutritional status following simultaneous resection of the liver and the pancreas were evaluated in an experimental animal model. Eighty SD rats were divided into four groups: control group (sham laparotomy, n = 20), 50% partial pancreatectomy group (Px, n = 20), 68% hepatectomy group (Hx, n = 20), and Px plus Hx group (n = 20). Five rats in each group were sacrificed for blood and liver collection on the first, second, third, and seventh postoperative days, respectively. One hour before sacrifice, 5-bromo-2-deoxyuridine (20 mg/kg/body weight) was injected intraperitoneally and BrdU-labeled nuclei in the liver were demonstrated immunohistochemically to allow examination of the mitotic response. Body weight increase rate (BWR), the liver wet weight (LWW), the ratio of the LWW to body weight, and the liver regeneration rate were calculated. Serum activity of alanine aminotransferase and levels of serum bilirubin and albumen were also measured. The LWW was relatively decreased after simple Px with no change in the BrdU labeling index or mitotic index. The highest peak of DNA synthesis of hepatocytes in the remaining lobes was markedly reduced on the first day after Hx + Px, with a delay in the hepatic regeneration response extending to the seventh postoperative day. Decrease in BWR in both the Px group and the Hx + Px group was observed on the first 3 postoperative days, with gain of BWR in the former case being slower. Removal of a portion of the pancreas can decrease hepatic weight under both normal and regenerative conditions. Simultaneous major resection of the liver and a portion of pancreas results in reduction and delay in the highest peak of DNA synthesis of hepatocytes in the remnant liver. We speculate that the pancreatic exocrine glands may play a distinct role in supporting the liver and in triggering hepatocyte proliferation.