Interstitial high dose-rate (HDR-) brachytherapy represents a very effective ablation technique not only for the treatment of liver malignancies. This technique is suitable for (1) large tumors as detailed planning with radiation oncologists allows to thoroughly cover extensive tumor volumes, (2) for lesions in close proximity to major vessels which are not suitable for thermal ablation due to heat sink effects, (3) for lesions in close proximity to heat vulnerable structures (e.g., stomach, duodenum, colon, heart, gall bladder), and (4) has less interference with breathing motion compared to stereotactic body radiotherapy (SBRT). Moreover, a higher dose-rate can be applied with less exposure of adjacent organs at risk thereby avoiding collateral damage. For most tumors, 15–25 Gy are administered to the lesion depending on the tumor entity.