Hepatic resection of metastatic tumor is a treatment option in selected patients. Resection margin is a prognostic factor of hepatic recurrence and survival. Although intraoperative radiation therapy (IORT) has been clinically useful in some gastrointestinal cancers, there is little information regarding its use following hepatic metastasectomy. In this study, a rat model was employed to evaluate histological changes and DNA synthesis as an indication of hepatic regenerative capacity following hepatectomy and liver IORT. All rats (N = 40) had a partial hepatectomy and were divided into four random groups: a nonradiated group and three groups of 1000, 2000, and 3000 cGy given by IORT. The only deaths occurred in the 3000 cGy group. Routine H and E staining of liver sections after 3, 6, and 10 days suggested progressive hepatocyte damage notably in the 3000 cGy group. Comparison of the final average liver weights at 10 days confirmed a diminished liver mass in the 2000 and 3000 cGy animals. DNA synthesis in hepatocytes measured by [3H]-thymidine label incorporation 3, 6, and 10 days after hepatectomy and IORT indicated a comparative and overall decrease in Day 6 peak activity between the three IORT groups. This study demonstrated delayed but substantial hepatic regeneration in the post-resected liver within the clinically useful IORT dose range (1000-2000 cGy) needed to control minimal residual tumor. This model has importance concerning the feasibility of IORT to the hepatic resection bed for patients where resection margins are inadequate.