Iodine-125 (125I) radioactive seed implantation brachytherapy is an emerging technique to treat pancreatic cancer, which, shown by clinical practice, offers benefits for pancreatic cancer patients in terms of pain relief, tumor progression control, quality of life improvement and survival time prolongation. Here, the authors present the current status and progress of 125I radioactive seed implantation brachytherapy in treatment of unresectable pancreatic cancer.