Treating colorectal liver metastases (CLMs) located at the hepatocaval confluence with surgery is challenging due to its complexity and associated high risks of perioperative mortality and morbidity. Moreover, thermal ablation techniques are sensitive to the "heat-sink" effect, which reduces their efficacy when tumors are in contact with major blood vessels. In this study we evaluated the feasibility and safety of an intraoperative high-intensity focused ultrasound (HIFU) device for destroying liver tissue volumes sufficiently large to consider treating CLMs at the hepatocaval confluence. Experiments were conducted on six pigs that were followed up to 19 days after the treatment. One HIFU ablation in each animal was created using a 370 s exposure at 100 W. Homogeneous HIFU ablations of liver tissues were safely created at the hepatocaval confluence around the hepatic veins (HVs) in all animals. The targeted HVs were similar to those of humans, with an average diameter of 9.1 ± 1.4 mm. The longest and shortest axes of the HIFU ablations were on average 44.5 ± 11.5 mm and 26.7 ± 4.9 mm, respectively. These values indicate that this device could destroy CLMs up to 2 cm in diameter. Doppler acquisitions, MRI and histological analysis confirmed that HIFU ablations were in contact with the inferior vena cava and extended to the HV wall and that blood flow was maintained. This in vivo preclinical study showed that intraoperative HIFU destruction of liver tissues at the hepatocaval confluence under Doppler ultrasound guidance could therefore represent a new therapeutic option for CLMs.