Objective To evaluate the safety and efficacy of surgical resection for the second and the third hepatic portal tumor. Methods The clinical data of 39 patients who underwent surgical resection of the second and the third hepatic portal tumor were analyzed from May 2012 to May 2017 in our hospital. Among them, there were 29 patients with primary liver cancer, 6 patients with hepatic hemangioma, 2 patients with focal liver hyperplasia, and 2 patients with liver metastasis from colon cancer. Results Right liver resection was performed in 11 patients, left liver resection in 7 patients, left outer lobe resection in 6 patients, right trefoil excision in 5 patients, Ⅴand Ⅷ segment resection in 4 patients, Ⅶ and Ⅷ segment resection in 4 patients, local resection in 2 patients. In the resection, there were 16 patients without interruption of hepatic inflow, 21 patients with interrupted portal blood flow, 2 patients with total hepatic blood flow occlusion. The operative time of the 39 patients was 150–270 min (mean of 190 min), the intraoperative blood loss was 100–2 000 mL (mean of 680 mL). Postoperative bile leakage occurred in 2 patients, bleeding occurred in 1 patient, and no liver failure occurred. Twenty-six patients were followed-up of 31 liver cancer patients, and the follow-up time was 3–40 months, the median time was 8 months. During follow-up period, 12 patients died, 9 patients died of tumor recurrence, 3 patients died from liver failure. Of 8 patients, 5 patients with benign liver disease were followed-up for 7–18 months with living healthy, and the median time was 9 months. Conclusion The risk of surgical resection of tumors invaded the second and the third hepatic portal is mainly the accurate functional assessment of residual liver and the correct treatment of the main branches of the hepatic veins.