Hepatic surgery in mice is challenging because of the delicate nature of the liver, lack of intravenous access, and risk of hemorrhage. In order to study the ability of the liver to regenerate after surgical resection, we developed a novel, rapid, and safe technique for partial hepatectomy in mice. We determined the relative contributions of the seven lobes of the mouse liver and resected the three most anterior lobes for a 68% hepatectomy. We used general anesthesia, a small upper midline incision, silk suture to tie off the lobes to be resected, warming pads and lights, as well as subcutaneous saline injection to ensure minimal morbidity. We have performed a safe two-thirds hepatic resection in 288 of 300 C57BL6 mice (96%). Perioperative mortality was due to technical error. Minimal long-term morbidity was appreciated. This technique may be applied to any type of hepatic resection in mice. In addition, the general operative technique and perioperative management of these mice may be applied to all types of murine intra-abdominal procedures used for surgical research.