Background: Despite substantial improvements in intra- and postoperative management of extended hemihepatectomy as the curative option for treatment of central liver tumors, the high morbidity and mortality rates accompanying the procedure still represent major obstacles. Mesohepatectomy preserves up to 35% more functional liver tissue than extended hepatectomy, but it has not been widely applied, perhaps because of its complexity as a resection method. Study Design: Forty-eight consecutive patients (29 men and 19 women) with centrally located liver tumors underwent mesohepatectomy. Peri- and postoperative morbidity and mortality rates were prospectively evaluated and analyzed. Mean age of the patients was 60.7 years. Indications for mesohepatectomy were liver metastasis (n = 29), hepatocellular carcinoma (n = 5), gallbladder carcinoma (n = 4), cholangiocellular carcinoma (n = 4), hemangioma (n = 2), and other benign diseases (n = 4). Results: Mean operative time was 238 minutes (range 65 to 480 minutes) and mean intraoperative blood loss was 1,120 mL (range 100 to 5,000 mL). Mean amount of intraoperative red blood cells and fresh frozen plasma transfusion was 3.6 U (range 1 to 12 U) and 3.8 U (range 2 to 14 U), respectively. Mean postoperative hospitalization was 15.8 days (range 6 to 104 days). Postoperative surgical complications were seen in 18.8% of patients (n = 9) and included liver failure (n = 1), intraabdominal abscess (n = 1), bilioma or bile leakage (n = 4), hemorrhage and hematoma (n = 2), peritonitis because of intestinal perforation (n = 1), and wound infection (n = 1). One patient (2%) died in the early postoperative phase from portal vein bleeding and disseminated intravascular coagulation, followed by liver failure. Conclusions: Compared with extended liver resection, mesohepatectomy clearly leads to less parenchymal loss. Although it is a technically difficult operation and requires special attention to prevent surgical complications, it is justified in selected patients with centrally located tumors and is a feasible and safe alternative to extended liver resection.