Objectives: To evaluate the feasibility and clinical value of CT-guided iodine-125 (I-125) brachytherapy for pain palliation in patients with breast cancer and bone metastases after external beam radiotherapy failure. Methods: From January 2014 to July 2016, a total of 90 patients, who had received the standard therapies for bone metastases but still suffered moderate-to-severe pain, were retrospectively studied. About 42 patients were treated with both I-125 brachytherapy and bisphosphonates (Group A), and 48 patients were treated with bisphosphonates alone (Group B). Results: In Group A, 45 I-125 brachytherapy procedures were performed in 42 patients with 69 bone metastases; the primary success rate of I-125 seed implantation was 92.9%, without severe complications. Regarding pain progression of the two groups, Group A exhibited significant relief in "worst pain," "least pain," "average pain," and "present pain" 3-day after treatment and could achieve a 12-week-remission for "worst pain," "least pain," "average pain," and "present pain." The morphine-equivalent 24-h analgesic dose at 3 days, 4 weeks, 8 weeks, and 12 weeks was 91 +/- 27, 53 +/- 13, 31 +/- 17, and 34 +/- 12 mg for Group A, and 129 +/- 21, 61 +/- 16, 53 +/- 15, and 105 +/- 23 mg for Group B. Group A experienced a lower incidence of analgesic-related adverse events and better quality of life than Group B. Conclusion: The CT-guided I-125 brachytherapy is a feasible and an effective treatment for the palliation of pain caused by bone metastases from breast cancer after external beam radiotherapy failure.