Approximately 20% of patients with spine metastasis present with unstable spine lesions. Vertebral body (VB) fractures represent a common therapeutic dilemma in patients with advanced stage cancer and limited survival time. The objective of this prospective study was to assess the safety and efficacy of Kypho-IORT and how to approach and deliver intraoperative radiotherapy (IORT) during kyphoplasty. This prospective trial assessed outcomes of Kypho-IORT in 16 patients who had potentially unstable, SINS scores (7-12), Bilsky grade (0-1) lesions, that were limited to the vertebral body ± one pedicle (sectors 1± 2/6 ) as per International Spine Radiosurgery Consortium (ISRC) anatomic classification system. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR was done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to Minimal distance from the source tip to OAR (Spinal Cord or Cauda Equina). Quality of Life Measurements were done using the QOL [EORTC QLQ-C30 (version 3)], the Brief Pain Inventory (BPI), Numerical Rating Pain Scale (NRPS), ambulation, and narcotic use pre- and post-procedure at 1-week, 3-month, 6-month, 9-month, 1-year, and 2-year intervals. Local outcomes were assessed via imaging every 3-months. Nine males and 7 females at a mean age of 53 years old were found to have a total of 22 involved vertebral bodies. This comprised of 11 thoracic and 11 lumbar levels originating from 13 (70%) radiosensitive and 9 (30%) radioresistant primaries. Mean treatment volume was 25.7 cc and mean treatment time was 12.6 minutes. At a median follow-up of 13 months, local control was 83%. Three patients had Kypho-IORT for 2 contiguous vertebrae and are currently without progression. Twelve patients had sector 1 (ISRC) lesions, and four patients were treated for sector 2 lesions which was associated with decreased local control (p=.06). 14 patients had Bilsky grade 0 lesions compared 2 patients with Bilsky grade 1 lesions. Three patients received previous external radiation treatment. Of the four patients who suffered a local relapse, 2 had sector 2 lesions, one had a Bilsky grade 1 lesion, and one had previous spine radiation. There were three adverse events as one patient had a cement leak, which was alleviated through a 2-week course of steroid treatment, and two patients experienced post-kypho fractures, one which required open surgery. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57±1.4 preoperative versus 3.57±2.57 postoperatively; p=0.0189). Patients also experienced a better quality of life with respect to bone metastasis-specific issues. Kypho-IORT is a safe treatment option for properly identified patients and results in excellent local control and significantly improved pain scores.